Of note, in vitro fertilization can, of course, overcome this problem as well. As mentioned above, the process of ovulation normally involves prostaglandin activity within the follicle. There are many different types of prostaglandins; several are involved in pathways that generate pain and inflammation. Pain relieving agents that belong to the class called non-steroidal anti-inflammatory drugs NSAIDs work by inhibiting prostaglandin activity.
A perennial source of worry among the infertility population is whether NSAID use can cause infertility due to luteinized unruptured follicle syndrome. For some women this may indeed be a small contributing factor in some cycles. However, it is not likely a major cause of infertility, especially since infertility rates appear unchanged by discontinuation of NSAID use.
However, since the theoretical risk is there, it makes sense to avoid NSAID use, if possible, around the time of ovulation. There is a lot of misleading information about it on the Internet, most of it published by patients themselves based upon their own infertility problems.
In truth, most of the patients that successfully conceive while attending fertility clinics do so via simple therapeutic approaches and do not require IVF. No matter which approach is taken, the possibility that any of several subtle abnormalities may be at play, including LUF, is taken into account and managed during therapy.
At Fertility Answers, we maintain a very high degree of surveillance over emerging data in all the fields of reproductive medicine. We are proud to bring successful, evidence-based, and cost-effective therapies to our patients in a compassionate and personable setting. Furthermore, written informed consent was obtained from the patients for the use of the videos. The patients were eligible for natural-cycle or minimally stimulated IVF-ET, and completed 1—3 treatment cycles at the clinic.
Thus, the patients desired an alternative method, and we offered them natural or minimally-stimulated cycles with re-assessment of their ovarian function. Couples with azoospermia were excluded, but couples with oligozoospermia were included. We identified 11, cycles 5, natural cycles and 6, minimally-stimulated cycles in which a single dominant follicle had grown.
Among the 11, cycles, we identified 1, cycles with 1, dominant follicles i. The IVF outcomes were compared to the regular IVF outcomes using oocytes that were normally aspirated from pre-ruptured follicles. Cycles in which the dominant follicle started to rupture at the oocyte retrieval i.
Flow chart of the study population. F: follicles; a : number represents the number of cycles; b : barely detectable follicles for puncture; c : due to technical difficulty. Follicle monitoring and triggering of the LH surge were performed as previously described On the morning of the planned oocyte retrieval, follicles were examined using transvaginal ultrasonography to determine whether the dominant follicle remained intact pre-rupture or had prematurely ruptured post-rupture.
Ruptured follicles were identified based on the total or subtotal loss of echo-free follicular fluid contents, relative to the most recent examination. If the ruptured follicle could be located within the ovary, based on the presence of an irregularly shaped central hypoechoic cavity, the physician ST punctured it using a G needle while taking care not to puncture the small follicles around the ruptured dominant follicle.
Representative needle aspirations are shown in Supplementary Videos 1 and 2. Most post-rupture dominant follicles had a 1—2-mm fluid-containing compartment that could still be punctured. After the puncture, the internal fluid was aspirated as thoroughly as possible by gently moving the needle tip around inside the space while repeatedly rotating the needle around its axis. Once back-flow had ceased, the needle was gently removed without any additional puncture and then flushed with a collection medium that contained heparin.
The oocyte retrieval procedures were recorded and stored as ultrasonographic movies, and were later reviewed to exclude the possibility of inadvertent puncture of nearby small follicles The aspirated fluid typically had a volume of approximately 0.
The maturity of the cumulus cells and oocytes was evaluated using a phase-contrast microscope. All embryos were cryopreserved when they had developed into good-quality blastocysts. The embryo was thawed and transferred during the following natural cycle or cycle with oestrogen and progestin supplementation All embryo transfers were single-embryo transfers, and were guided using transvaginal ultrasonography. Photographs of COCs from post-rupture dominant follicles were available to evaluate the maturation status of the cumulus cells and intercellular substances.
Five hundred photographs of COCs from the pre-rupture follicle were randomly selected as controls, and we found that of those photographs were of sufficient quality to perform the evaluation. The maturation status of the cumulus cells was classified into four levels mature, immature, over-mature, and others based on the criteria reported by Guelman and Patrizio 17 Supplementary Fig.
A COC with a sunburst-like corona radiata and a well-expanded cumulus was considered mature. A COC with compact cumulus cells in a cobble stone-like arrangement was considered immature. A COC with luteinised cells surrounded by massive gelatinous-like substances was considered over-mature. In over-mature cases, there was a reduced number of cumulus cells and it was not possible to distinguish between the corona and the cumulus.
Logistic regression analysis was used to identify clinical factors that were associated with post-rupture follicle status. All data generated or analysed during this study are included in this published article and its Supplementary Information Files. Craft, I. Ovum retention in the human. Fertil Steril 34 , — Stanger, J.
Failure of human oocyte release at ovulation. Fertil Steril 41 , — Russell, D. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Straus, J. Barbieri Ch. Fulop, C. Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice.
Development , — Davis, B. Anovulation in cyclooxygenasedeficient mice is restored by prostaglandin E2 and interleukin-1beta.
Shindo, T. ADAMTS a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function. Robker, R. Varani, S. Knockout of pentraxin 3, a downstream target of growth differentiation factor-9, causes female subfertility. Mittaz, L. Adamts-1 is essential for the development and function of the urogenital system. Tan, K. Primary ovarian pregnancy. Am J Obstet Gynecol , — Article Google Scholar. Bontis, J. Human reproduction 12 , — Marret, H.
Case report and review of the literature: primary twin ovarian pregnancy. The purpose of this study was to examine possible effects of the selective COX-2 inhibitor, rofecoxib RX , on ovulation in a group of healthy women with regular menstrual patterns. Nineteen healthy women with no prior history of gynaecological or reproductive disorders volunteered for the study. None of the women were using hormonal contraception or any other medication for at least 2 months prior to the study and all had a history of regular menstrual cycles 27—34 days.
Thirteen women were included in the study. In the placebo group, one woman was para 3, two were para 2, one was para 1 and three were para 0. In the treatment group, four women were para 2, one was para 1 and one was para 0. Each woman was monitored for 2—4 consecutive menstrual cycles. Cycle 1 was the control cycle; cycle 2 was the treatment cycle RX or placebo ; cycles 3 and 4 were follow-up cycles in certain cases.
Menstrual cycle day 1 CD 1 corresponded to the first day of the bleeding period. During cycle 1, blood samples for LH, FSH, oestradiol and progesterone measurement were taken every 3—4 days. Ultrasonic scans were performed with a 5 MHz transvaginal transducer. All scans were performed by two of the authors M. Only women with a demonstrable ovulatory pattern, in concordance with predefined inclusion parameters, were treated with RX or placebo in a second cycle which followed immediately.
During the treatment cycle, blood samples were taken initially every 3—4 days. Beginning at CD 8—10, transvaginal scans were performed daily until a dominant follicle 14—16 mm was visible. The investigators were not aware of which substance the participants received until all treatment cycles were completed.
Follicle rupture was pre-defined as a decrease in mean follicular diameter of at least 3 mm Coetsier and Dhont, and appearance of intrafollicular echos. Follicle rupture was pre-defined as a decrease in mean follicular diameter of at least 3 mm Coetsier and Dhont, Women with abnormal findings during the treatment cycle were monitored in subsequent cycles until resumption of normal ovulatory pattern was seen.
All hormone samples from the treatment cycles were analysed after completion of the study. All analyses were performed in duplicates. Ultrasound and endocrinological results during the treatment cycle, in the placebo and RX groups, were compared, within defined time intervals, relative to the highest detectable LH values defined as day 0. Serum sample duplicates were analysed and the mean of the two values was used for further analysis.
Grouping factors were defined as treatment and day of cycle in relation to the LH peak repeated measures. The software used for all analyses was Stat View 5. For all statistical results reported, the critical P -value was set to 0. The dominant follicles were detected between CD 7—12 and follicle diameters increased consistently and linearly in both the placebo and treatment groups until the day of the LH peak Figure 1. The mean day of follicular rupture Figure 3 , but not the day of the LH peak Figure 4 , differed significantly between the placebo and RX groups.
Two subjects in the RX group had follicular rupture 36—48 h after the LH peak and were therefore classified as having normal ovulatory patterns. This cystic structure collapsed during the periovulatory phase during cycle 3. The subject experienced intense abdominal pain at this time and the collapsed cyst was visible until CD 7 of cycle 4.
This case was omitted in statistical analyses concerning follicle diameter and rupture. No other side-effects were experienced in either placebo or RX groups. No significant differences in the analysed intra-individual hormone parameters were seen. Thus, no delay in decreased progesterone concentration during the luteal phase Figure 5 , or in oestradiol rise in the follicular phase data not shown , was seen. The regularity of the subsequent menstrual cycle cycle 3 was unchanged in all women.
The present study examined the effects of a novel specific COX-2 inhibitor, RX, on ovulation in a group of healthy women. This inhibitor, RX, exerts anti-inflammatory, antipyretic and analgesic effects but with lower levels of gastrointestinal GI side effects as compared with non-specific COX inhibitors Hawkey et al.
Rofecoxib was administered in a double-blind fashion, thereby eliminating possible subject and investigator bias. All women in placebo group ovulated within 36 h of the LH surge. No effect on peripheral sex steroid or gonadotrophin concentrations was seen. In this type of study, in the human female, it is critical to use acceptable methods when monitoring follicular development.
Invasive methods such as laparoscopy have been used to monitor changes in the ovulatory cycle Marik and Hulka, The dominant follicle is first discernible by transvaginal ultrasound after CD 6 and there seems to be no difference in dominant follicle growth rate and appearance between imminent ovulatory and non-ovulatory cycles prior to expected ovulation Gore et al. Daily ultrasound examinations together with serial hormonal analyses, however, are required in order to minimize misinterpretations of follicle development during the periovulatory period Petsos et al.
The two COX enzymes are located in different intracellular areas and use different pools of arachidonate in distinct metabolic pathways Morita et al. Non-steroidal anti-inflammatory drugs assert their non-specific inhibition with varying potency and selectivity Cryer and Feldman, Pervading characteristics of the influence of PG synthesis inhibition on ovulation include evidence of ovulation without conception capability and LUF, a clinical phenomenon involving ovulatory failure despite a preceding LH peak, rise in luteal phase progesterone and secretory endometrium.
The definition and prevalence of LUF, as well as luteal phase follow-up in earlier studies, have varied Zaidi et al. Varying effects on luteal progesterone concentrations have been reported Hamilton et al. The effect of the non-selective PG synthesis inhibitor indomethacin, when administered concomitantly with HCG as an ovulatory stimulus, was investigated Killick and Elstein, and a Reports on women taking continuous NSAIDs, such as diclofenac, have described infertility and a high prevalence of LUF, some with subovulatory progesterone values in the mid-luteal phase Smith et al.
The negative effects of NSAIDs on ovulation appear to be reversible as studies of women taking this type of medication, on a long-term basis, demonstrate signs of normal ovulation within one menstrual cycle after medication interruption Akil et al. In common with an earlier study Killick and Elstein, , we examined a group of women with no prior history of infertility or any other somatic illness.
Contrary to Killick and Elstein Killick and Elstein, , we used no artificial ovulatory stimulus and hormone levels in serum were followed regularly during the entire study; daily during the treatment period. Despite the delay in follicular rupture, no alterations in serum progesterone concentrations were demonstrated. Rofecoxib has demonstrated similar mechanisms of inhibition as another selective COX-2 inhibitor, NS, in vitro Ouellet and Percival, ; Chan et al.
We have recently demonstrated that NS reduced ovulation frequency in vivo and in vitro in the rat Mikuni et al. A dose-dependent decrease in PGE 2 synthesis was seen in vivo but the ovulation rate was only affected by the highest dose tested. This suggested that prostanoids must be reduced below a certain threshold level in order to inhibit ovulation.
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