Corpus Luteum Insufficiency Research Articles

The effect of Bushen Culuan Decoction on anovulatory infertile women among 6 different diseases: a study protocol for a randomized, double-blinded, positively controlled, adaptive multicenter clinical trial

BackgroundAnovulation is one of the main causes of female infertility. This study will evaluate the effectiveness and safety of Bushen Culuan Decoction for anovulatory infertility caused by six diseases, including anovulatory abnormal uterine bleeding, polycystic ovarian syndrome, hyperprolactinemia, luteinized unruptured follicle syndrome, corpus luteum insufficiency, and premature ovarian insufficiency.MethodsThis is a randomized, double-blinded, double-dummy, parallel, positively controlled, adaptive, multicenter clinical trial. All participants will be randomly allocated by a central randomization system to the treatment group or the control group in a 1:1 ratio. The treatment group will undergo a 14-day treatment with Bushen Culuan Decoction 13 g three times a day and a 5-day treatment with clomiphene citrate placebo tablets 50 mg once a day starting on day 5 of every menstrual period. The control group will undergo a 14-day treatment with Bushen Culuan Decoction placebo 13 g three times a day and a 5-day treatment with clomiphene citrate tablets 50 mg once a day from day 5 in every menstrual period. The whole treatment will last through 3 menstrual periods or 6 menstrual periods, depending on whether ovulation is regained in the first 3 menstrual periods. All statistical analyses will be performed in SPSS 21.0 (SPSS, Chicago, Illinois, USA), and a p value < 0.05 will be considered statistically significant.DiscussionThe objective of this RCT is to evaluate whether Bushen Culuan Decoction enables a higher pregnancy rate than clomiphene citrate in women with anovulatory infertility and to identify the anovulatory diseases for which Bushen Culuan Decoction has higher effectiveness .This study has been approved by the Medical Ethics Committee of Xiyuan Hospital China Academy of Chinese Medical Sciences (No. 2017XLA037-2). The results of this study will be offered for publication in peer-reviewed journals.Trial registrationClinicalTrials.gov NCT03709849. Registered on 19 November 2018.

Biomarker Validation of a New Case Definition of Menstrual Cycle-Associated Syndrome (MCAS) Opinion Paper

There are different case definitions of premenstrual syndrome, one proposed by the American College of Obstetricians and Gynecologists (ACOG) and another based on the Daily Record of Severity of Problems (DRSP) scores. Here we review our recent findings indicating that the gold-standard methods to assess PMS, including ACOG, provide a high degree of false-negative findings. We propose a new case definition of the Menstrual Cycle-Associated Syndrome (MCAS), which is characterized by increased DRSP scores during the menstrual cycle and symptom that increases the week prior to the menses. The MCAS case definition was externally validated by diverse biomarkers including plasma levels of progesterone and estradiol, chemokines (e.g. CCL2, CCL5 and CCL11), epidermal growth factor, hydroperoxides, paraoxonase 1 activity and complement C4. These biomarkers as well as IgA responses to Gram-negative bacteria are significantly associated with the DRSP and its subdomains including depression, anxiety, and physiosomatic symptoms(fatigue, pain). In conclusion, we propose, a) to use the MCAS diagnosis as an indicant of menstrual cycle-related symptoms; and b) to examine the associations of the time series in the DRSP and its subdomains and those in biomarkers including distributed lag models. Aberrations in the uterine-chemokine-brain-axis underpin the pathophysiology of MCAS whereby suboptimal pre-ovulatory follicular development coupled with a relative corpus luteum insufficiency may drive increased chemokine production, lowered antioxidant defenses, neuro-oxidative stress pathways, and increased bacterial translocation. As such, we have delineated new drug targets for the treatment of MCAS. This opinion paper reviews new possible treatments that should be trialed in MCAS.

Lowered Plasma Steady-State Levels of Progesterone Combined With Declining Progesterone Levels During the Luteal Phase Predict Peri-Menstrual Syndrome and Its Major Subdomains.

BackgroundIt is unknown whether lowered steady state levels of sex hormones coupled with changes in those hormones during the menstrual cycle are associated with premenstrual syndrome (PMS).ObjectiveTo examine associations between levels of progesterone and oestradiol during the menstrual cycle and PMS considering different diagnostic criteria for PMS.MethodsForty-one women aged 18–45 years with a regular menstrual cycle completed the Daily Record of Severity of Problems (DRSP) for all 28 consecutive days of the menstrual cycle. Blood was sampled at days 7, 14, 21, and 28 to assay oestradiol and progesterone.ResultsWe developed a new diagnosis of peri-menstrual syndrome, which is characterized by increased DRSP severity in pre and post-menstrual periods and increased scores on the major DRSP dimensions, i.e., depression, physio-somatic symptoms, breast tenderness and appetite, and anxiety. This new diagnosis performed better than classical diagnoses of PMS, including that of the American College of Obstetricians and Gynecologists (ACOG). Lowered steady state levels of progesterone, when averaged over the menstrual cycle, together with declining progesterone levels during the luteal phase predict severity of peri-menstrual symptoms. Steady state levels of oestradiol and declining oestradiol levels during the cycle are also related to DRSP severity although most of these effects appeared to be mediated by progesterone.ConclusionA significant increase in menstrual-cycle related symptoms can best be conceptualized as “peri-menstrual syndrome” and may result from insufficient progesterone production (relative corpus luteum insufficiency), which, in part may result from lowered oestradiol production indicating suboptimal pre-ovulatory follicular development.

The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots. Effects of extracts of chasteberry (Vitex agnus-castus) as a solution

The dried fruits of the chaste tree Vitex agnus-castus (VAC) were traditionally used by monks as a substitute for pepper and was therefore also called Monk’s pepper. For the last 50 years it is commercially provided for the treatment of premenstrual symptoms, particularly to prevent premenstrual mastodynia (mastalgia). Most studies were performed with the preparation containing an aqueous/ethanolic ectract BNO 1095. A number of placebo controlled studies gave proof that extracts of VAC had beneficial effects on premenstrual breast pain. This breast sensation is induced by latent hyperprolactinemia which is characterized by secretory episodes of prolactin release by the pituitary in response to stress and deep sleep phases. This latent hyperprolactinemia induces also often a corpus luteum insufficiency which is a common reason for infertilty. It is well accepted that prolactin release can be reduced by dopamine and dopaminergic drugs. The efficacy of VAC extracts to ameliorate prolactin induced premenstrual mastodynia was therefore suggestive that VAC may contain dopaminergic compounds. Indeed, a number of diterpenes were identified that bound to recombinant Dopamine receptors of the 2 subtype which are present in pituitary lactotropes and which mediate the inhibitory effects of dopamine and dopaminergic drugs on pituitary prolactin release. Consequently, prolactin release in vitro from dispersed pituitary cells and in vivo in rats and postmenopausal women was inhibited by VAC 1095. Placebo controlled studies proved also the efficacy of VAC extracts to ameliorate premenstrual symptoms. In several placebo-controlled studies a clear relation between reduction of breast pain and reduction of serum prolactin levels could be established. In addition VAC extracts was also highly effective in women suffering from fibrocystic mastopathy. In many of these women serum prolactin levels were also elevated and reduced by VAC extracts. The results from all trials suggested that VAC extracts ameliorated premenstrual symptoms including mastodynia, premenstrual dysphoric disorder and latent hyperprolactinemia. Cystic mastopathy and sterility due to corpus luteum insufficiencies were also beneficially influenced. Adverse events with VAC were mild and generally infrequent.

Feasibility of transabdominal Doppler ultrasonography for studying ovarian blood flow characteristics in cycling gilts.

The aim of this study was to assess ovarian blood flow characteristics by applying transabdominal color Doppler ultrasonography during the course of the estrous cycle in gilts. Estrus and ovulation were synchronized in 15 pubertal gilts. During their consecutive spontaneous estrous cycle the gilts were sonographically scanned daily and ovarian blood flow was determined by imaging perfused areas of the ovarian hilus and the ovarian tissue. Recorded video clips were then analyzed for the parameters perfused area (Amix), blood flow velocity (vmix) as well as resistance (RIvmix) and pulsatility index (PIvmix) using the software PixelFlux®. All blood flow parameters showed an estrous cycle dependent course, with Amix and vmix being highest in diestrus, followed by proestrus, while RIvmix and PIvmix patterns were inversely proportional. Transabdominal color Doppler ultrasonography proved feasible to study ovarian perfusion characteristics in pubertal gilts. The ovarian blood flow was dependent on the stage of estrous cycle and highest in diestrus. The results of this study encourage the use of color Doppler ultrasonography to also investigate reasons of ovary-caused infertility including corpus luteum insufficiency or seasonal effects on ovary function.

Changes in Local Immunity Factors in Women with Pre-Existing Cervical Disease and Benign Ovarian Tumors

The objective of the research was to study the indices of local immunity in relation to the hormonal state of the body in women with benign ovarian tumors and pre-existing cervical diseases.Materials and methods. The concentration of major gonadotropic and steroid hormones during the female ovarian and menstrual cycle, as well as individual local immunity factors of proinflammatory cytokines and secretory immunoglobulin A was studied in 40 patients with benign ovarian tumors and pre-existing cervical diseases.Results and discussion. In the second phase of the ovarian and menstrual cycle, a significant reduction (by 3.0 times) in the concentration of progesterone and relative hypoestrogenism (by 1.5 times as compared to the control data) were found. Anovulation was observed in 40.00% of cases and corpus luteum deficiency syndrome was diagnosed in 62.5% of women. The assessment of secretory immunoglobulin A concentration allowed us to note (along with the hypersecretion of proinflammatory cytokines) an increase in this marker in half of the examined women in the presence of chronic cervicitis and vaginitis, candidiasis and viral lesion - along with the activation of proinflammatory cytokine depression of secretory immunoglobulin A synthesis as compared to the control data.Conclusions. Local immunity changes in women with benign ovarian tumors and pre-existing cervical diseases are accompanied by abnormalities of the hormonal profile and the association of maladaptive changes in the system of local immunity manifested by fluctuations in the level of secretory immunoglobulin A during the secretory phase of the menstrual cycle and an increase in proinflammatory cytokine synthesis. The results of the conducted study allowed us to note a significant increase in the concentration of secretory immunoglobulin A along with the activation of proinflammatory cytokine synthesis in most women with benign ovarian tumors and pre-existing cervical diseases which confirms the development of acute inflammatory reactions on the background of the existing hormonal imbalance. In patients with pre-cancerous cervical diseases, there was a tendency toward depression of secretory immunoglobulin A synthesis, a significant inhibition of local immunity, especially typical for cervical intraepithelial neoplasia on the background of human papillomavirus infection. All the aforementioned data confirm the formation of secondary immunodeficiency in this category of patients.

Methods of prolonging a pregnancy threatened with preterm labour

Both prolonged and shortened pregnancies carry the risk of increased mortality of the offspring. The main causes of early delivery are genetic factors, bacterial and viral infections, corpus luteum insufficiency and pathologies of the placenta. Antepartum luteolysis is due to the activity of prostaglandin F2α. A decrease in the progesterone concentration activates the sensitivity of the uterine muscles to oxytocin. Calcium ions move into the myocytes and bind to calmodulin, starting enzymatic reactions necessary for muscle contraction. Oxytocin promotes prostaglandin F2α release. Cholesterol and magnesium stimulate the binding of oxytocin to its receptors. A premature delivery is caused by a disorder of the balance between contractility and relaxation of the myometrium, which is regulated by many signalling pathways. Birth in humans can be postponed by the use of many different tocolytic medications, β-adrenergic drugs (ritodrine, hexoprenaline, fenoterol, terbutaline), magnesium salts, prostaglandin synthesis inhibitors (indomethacin, naproxen), pentoxifylline, metoprolol, calcium antagonists – calcium channel blockers (nifedipine), oxytocine antagonists (atosiban), nitric oxide donors (nitroglycerin) as well as progesterone and its synthetic analogs. In dogs and cats, in the presence of endogenous hormone deficiency, progesterone and its derivatives (gestagens) are recommended. In small animals with the risk of premature delivery, terbutaline has successfully been used. Premature delivery is a serious problem in both human and veterinary medicine, and experience from human medicine is being gradually introduced into veterinary practice.

Experience the use of phytopreparations Cyclodynon® in patients with insufficiency of corpus luteum and hyperprolactinemia

Complex clinical and laboratory examination among 20 patients aged 25 to 41 years with relative hyperprolactinemia suffering from menstrual irregularities of various kinds was performed. The control group consisted of 15 healthy women. In patients with corpus luteum insufficiency, caused by hyperprolactinemia, in order to correct existing disorders phytopreparation agnucaston (Cyclodynon®) was used.The results showed that agnucaston (Cyclodynon®) effectively reduced the increased secretion of prolactin, the drug increases cyclic secretion of progesterone in the luteal phase of the cycle, which helps normalize the menstrual rhythm.The authors concluded that agnucaston (Cyclodynon®) can be considered an alternative to treatment with other stimulators of dopamine receptors in their intolerance in patients with hyperprolactinemia of non-tumor genesis.

Preliminary study on relationship of disease-syndrome-symptom of ovulatory disorder infertility based on factor analysis

In this study, the clinical data of 240 cases of data acquisition on ovulation in patients with anovulatory infertility. Using the method of factor analysis, summed up the distribution situation of various syndromes and the relationship of disease-syndrome-symptom. From the study we found that polycystic ocary syndrome > premature ovarian failure > corpus luteum insufficiency > luteinized unruptured follicle syndrome > hyperprolactinemia > anovulatory dysfunctional uterine bleeding. Using the factor analysis method, the syndromes of anovulatory infertility were divided into six types and the distribution proportion of them is: kidney Yang deficiency and blood stasis > kidney Yang deficiency > kidney Yin deficiency and blood stasis > kidney Yin deficiency and liver Qi stagnation syndrome > kidney Yang deficiency and phlegm dampness stagnation > kidney Yin deficiency. By means of statistics, the traditional Chinese medicine (TCM) symptoms as abdomen pain before menstrual onset, obfuscation colour, cold lower abdomen, insomnia, fatigue, eyes dark, face dark or ring lip dark, before and after menstruation breast swelling, chest tightness, irritable insomnia, depression and lower abdomen pain during menstruation etc contribute high degree in the process. Polycystic ovary syndrome and premature are the main causes of ovulatory disorder infertility and the disease incidence rate assumed the tendency which rose year by year. The treatment of the disease of kidney yang deficiency syndrome scales biggest the disease degree of contribution. Blood stasis is the important factor in the process of pathogenesis evolution. In the study of disease distribution, we found that symptom distribution trend roughly the same and the same symptom severity in different diseases with different, which provides experience for the theory-different diseases with the same therapeutic method. These conclusions provide guidance and reference evidences for clinic practice.

Stereological estimation of ovarian volume and number of follicles in low dose of Vitex agnus castus treated mice

Vitex agnus castus (VAC) has been proven to have a wide range of biological activities. It is commonly used in the treatment of menstrual disorders resulting from corpus luteum deficiency, including premenstrual symptoms and spasmodic dysmenorrheal, for certain menopausal conditions, and for insufficient lactation. The aim of this study was to investigate the effects of low dose of VAC essential oil on ovarian volume and oocyte number in mice by stereological technique. In this study 10 young adult female BALB/c mice were randomly divided into two groups: group 1 as control group and group 2 which received 75 mg/kg VAC essential oil via gastric gavage for seven consecutive days. At the eighth day, animals were euthanized and the ovaries were quickly removed, weighted and fixed in buffered formalin. The samples were processed by routine and standard paraffin embedding and using the isotropic Cavalieri design were sectioned. Eight to twelve sections from each ovary were sampled through systematic random sampling and were stained by H&E. The volume of the ovary (cortex and medulla) was estimated by unbiased stereological methods and the numbers of the follicles were estimated using an optical disector. The results showed that volume of ovaries and ovarian cortex was significantly increased in treated mice compared to control but volume of ovarian medulla didn’t changed. Stereological result revealed that number of primordial follicle was decreased in treated group but this changes was not significant (P>0.05) and number of preantral follicles was significantly increased in treated mice (P 0.05). It can be concluded that VAC essential oil can affected structure and maturation of ovarian follicles even in low dose.

Fixed-time deep uterine insemination in PGF2α-synchronized goats

The aim of this investigation was to optimize fixed-time insemination in goats by clustering ovulations in prostaglandin F2α-synchronized goats either with gonadotropin releasing hormone (GnRH) or human chorionic gonadotropin (hCG). The underlying intention was to reduce the incidence of short cycles by providing a more sustained stimulation of the corpus luteum by substituting the commonly used GnRH with longer-acting hCG. It was conjectured that this might render the corpus luteum less prone to premature regression. Sixty pluriparous does were administered 5 mg of the prostaglandin F2α preparation dinoprost (Dinolytic; Pharmacia and Upjohn, Erlangen, Germany) during the luteal phase of the estrous cycle. Twenty of these does were administered 0.004 mg of the GnRH analog buserelin (Receptal; Intervet, Unterschleissheim, Germany) 48 hours later; another 20 does received 500 IU hCG (Chorulon; Intervet, Unterschleissheim, Germany) instead. Sixteen hours later the does were inseminated with frozen-thawed semen. The remaining 20 does served as controls and were inseminated 16–18 h after the onset of detected estrus. All 60 treated goats displayed estrous symptoms, the time of onset being similar for all groups (42.6, 37.6, and 40.5 hours after treatment for GnRH-treated, hCG-treated, and control does, respectively). The duration of estrus in the GnRH-treated group was 10 h less than in the other groups (45.1 vs. 56.4 and 54.4 h, P < 0.05). The number of ovulations (assessed by ultrasound monitoring) did not differ among groups (2.4, 2.1, and 2.5, P > 0.05). Monitoring of serum progesterone revealed that the incidence of corpus luteum insufficiency was significantly higher in GnRH- and hCG-treated does than in the control group (40% and 35% vs. 5%, P < 0.05). The pregnancy rate was 50% in the GnRH and 35% in the hCG group as compared with 60% in the controls. Corresponding kidding rates were 40%, 35%, and 60% (P > 0.05). When disregarding does with corpus luteum insufficiency, pregnancy rates would have been 83%, 54%, and 63%, and kidding rates 67%, 54%, and 63%, respectively. The average number of kids born was 1.88, 1.71, and 1.83, respectively (P > 0.05). It may be concluded that fixed time insemination of cycling does treated with prostaglandin F2α during the luteal phase, followed by ovulation induction with GnRH or hCG, would be an effective management tool if it were possible to control the high incidence of corpus luteum insufficiency. The attempt to achieve this by substituting GnRH with hCG, was not met with success. Until a solution for the problem has been found, it is advisable to inseminate prostaglandin-synchronized does 16–18 hours after the onset of detected estrus.

Der Stellenwert des Mönchspfeffers (Vitex agnus-castus) in der gynäkologischen Endokrinologie

The status of chaste tree ( VITEX AGNUS-CASTUS) in gynaecological endocrinology Extracts of the dried fruits of the chaste tree ( VITEX AGNUS-CASTUS, VAC) contain dopaminergic compounds which are inhibitory to pituitary prolactin release. The development of premenstrual mastalgia as well as of fibrocystic breast changes involves an action of prolactin. Hence, treatment with VAC is helpful to prevent these mammary gland symptoms. Prolactin is also involved in the function of the corpus luteum and patients with a latent hyperprolactinemia often suffer from a corpus luteum insufficiency where treatment with VAC extracts may also be helpful to improve fertility.

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice

The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicer(d/d)) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer(d/d) mice was caused by corpus luteum (CL) insufficiency and resulted, at least in part, from the impaired growth of new capillary vessels in the ovary. We found that the impaired CL angiogenesis in Dicer(d/d) mice was associated with a lack of miR17-5p and let7b, 2 miRNAs that participate in angiogenesis by regulating the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase 1. Furthermore, injection of miR17-5p and let7b into the ovaries of Dicer(d/d) mice partially normalized tissue inhibitor of metalloproteinase 1 expression and CL angiogenesis. Our data indicate that the development and function of the ovarian CL is a physiological process that appears to be regulated by miRNAs and requires Dicer1 function.

Vitex agnus castus

Vitex agnus castus L. (VAC) [Verbenaceae] is a deciduous shrub that is native to Mediterranean Europe and Central Asia. Traditionally, VAC fruit extract has been used in the treatment of many female conditions, including menstrual disorders (amenorrhoea, dysmenorrhoea), premenstrual syndrome (PMS), corpus luteum insufficiency, hyperprolactinaemia, infertility, acne, menopause and disrupted lactation. The German Commission E has approved the use of VAC for irregularities of the menstrual cycle, premenstrual disturbances and mastodynia. Clinical reviews are available for the efficacy of VAC in PMS, cycle disorders, hyperprolactinaemia and mastalgia, but so far no systematic review has been published on adverse events or drug interactions associated with VAC. Therefore, this review was conducted to evaluate all the available human safety data of VAC monopreparations. Literature searches were conducted in six electronic databases, in references lists of all identified papers and in departmental files. Data from spontaneous reporting schemes of the WHO and national drug safety bodies were also included. Twelve manufacturers of VAC-containing preparations and five herbalist organisations were contacted for additional information. No language restrictions were imposed. Combination preparations including VAC or homeopathic preparations of VAC were excluded. Data extraction of key data from all articles reporting adverse events or interactions was performed independently by at least two reviewers, regardless of study design. Data from clinical trials, postmarketing surveillance studies, surveys, spontaneous reporting schemes, manufacturers and herbalist organisations indicate that the adverse events following VAC treatment are mild and reversible. The most frequent adverse events are nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritus and erythematous rash. No drug interactions were reported. Use of VAC should be avoided during pregnancy or lactation. Theoretically, VAC might also interfere with dopaminergic antagonists. Although further rigorous studies are needed to assess the safety of VAC, the data available seem to indicate that VAC is a safe herbal medicine.

Cyclic menstruation-like bleeding during denied pregnancy. Is there a particular hormonal cause?

Objective. To investigate whether particular hormonal patterns could explain the persistence of cyclic menstruation-like bleeding during denied pregnancies.Methods. Hormone measurements were performed immediately after delivery in a total of 28 subjects with denied pregnancies. The results were studied in three patient subgroups: subjects with any cyclic bleeding during pregnancy (n = 22), subjects with cyclic bleeding during pregnancy until the delivery date (n = 7) and subjects with amenorrhea (n = 6). These data were compared with those of a control group (n = 126). In some of the women who reported cyclic bleeding, hormone assessments were also done once the lactation period ended.Results. For estradiol, free estriol and progesterone, no more than two values in each group were outside the 95% confidence interval of the control group. Several results for prolactin were remarkably lower. The findings for human chorionic gonadotropin, free testosterone, dehydroepiandrosterone sulfate, α-fetoprotein and thyroid-stimulating hormone were almost all within the 95% confidence interval. In seven subjects, abnormal results were obtained for the gondaotropin-releasing hormone/thyrotropin-releasing hormone test and the metoclopramid test after delivery and lactation. All of these subjects showed signs of corpus luteum insufficiency. In five subjects, evidence of hyperprolactinemia was found.Conclusion. Results revealed that hormonal patterns assessed immediately after delivery do not provide any causal explanation for the cyclic menstruation-like bleeding that occurs during denied pregnancies. Hormone assessments performed after the lactation period, i.e. during a normal menstrual cycle, showed a number of abnormalities. However, a causal relationship could not be drawn.

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Effectiveness of Vitex agnus-castus preparations

The prolactin-inhibiting effect of ACF-preparations, which is due to dopaminergic activities, has been shown in humans too and gives a pharmacological rationale for the clinical effects observed in the different indications (2, 11, 25, 26, 35, 41). Confirmation of efficacy in the treatment of mastalgia has been best endorsed by two recently published double-blind studies conducted according to the principles of GCP (14, 41). One double-blind study, several open and postmarketing surveillance studies have shown that the premenstrual syndrome, or individual symptoms, can be influenced positively (3, 6, 7, 9, 19, 21, 37). Design shortcomings in a second double-blind study should be eliminated in future studies in this indication to improve the body of evidence (18). Hither to there has been one controlled double-blind study of cycle disorders in the case of corpus luteum insufficiency with significant results and a number of non-controlled open studies (1, 4, 15, 16, 20, 24, 26, 27, 32, 35, 36). The high success rates in the open studies indicate therapeutic effects, and it should be possible to reproduce these results under double-blind conditions. The success rates on fertility disorders should be confirmed in controlled double-blind studies (10, 33, 34).

Ovulation induction disrupts luteal phase function.

Abnormalities in the luteal phase have been detected in virtually all the stimulation protocols used in in vitro fertilization, on both the hormonal and endometrial levels. Supraphysiological follicular or luteal sex steroid serum concentrations, altered estradiol: progesterone (E2/P) ratio, and disturbed luteinizing hormone pituitary secretion leading to corpus luteum insufficiency or a direct drug effect have been postulated as the main etiologic factors. Luteinizing hormone supports corpus luteum function, and low LH levels have been described after human menopausal gonadotropin treatment, after gonadotropin-releasing hormone (GnRH)-agonist treatment, or after GnRH-antagonist treatment. These low luteal LH levels may lead to an insufficient corpus luteum function and consequently to a shortened luteal phase or to the low luteal progesterone concentrations frequently described after ovulation induction. A direct effect of the GnRH agonist or GnRH antagonist on human corpus luteum or on human endometrium and thus on endometrial receptivity cannot be excluded, as GnRH receptors have been described in both compartments. Endometrial histology has revealed a wide range of abnormalities during the various stimulation protocols. In GnRH-agonist cycles, mid-luteal biopsies have revealed increased glandulo-stromal dyssynchrony and delay in endometrial development, strong positivity of endometrial glands for progesterone receptors, decreased alphavbeta3-integrin subunit expression, and earlier appearance of surface epithelium pinopodes. These factors suggest a shift forwards of the implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been well established, at least in cycles using GnRH agonists.

Estradiol-17β and progesterone in the peripheral blood plasma of goats following superovulation with a single dose of pFSH, hMG or eCG

During the breeding season, 42 adult German Improved Fawn nanny goats were superovulated with a single dose of pFSH, hMG or eCG at the end or a single application of pFSH 36 h before the end of synchronization treatment using flugestone acetate (FGA). Plasma sampling was performed immediately before and 1 h after gonadotrophin treatment, twice daily during pre-estrus and estrus and once daily during post-estrus in order to determine peripheral estradiol-17β and progesterone levels. During that period, ovarian dynamics was followed by serial ultrasound scans (8 h interval during pre-estrus and estrus and once daily during post-estrus). Estradiol-17β profiles differed between the treatment groups exhibiting significantly positive correlations between the mean estradiol-17β concentrations and the numbers of developing large and medium-sized follicles during estrus. The early bolus application of FSH 36 h before the end of synchronization treatment induced an additional advanced estradiol-17β peak during gestagen dominance. A sharp decrease of estradiol-17β at the end of estrus seems to play a major role for normal luteal development. Progesterone profiles during the early luteal phase revealed high premature luteal regression. An early progesterone increase was accompanied by low premature regression rates. Although simple B-mode ultrasonography is suitable to follow follicular growth patterns and to determine the ovulation rate following different superovulation regimen endocrinological supervision is required in order to detect a premature corpus luteum insufficiency.