Oral clomiphene citrate and vaginal progesterone suppositories in the treatment of luteal phase dysfunction: a comparative study

Preimplantation loss of fertilized human ova: estimating the unobservable

Wilcox AJ et al., 2020 · Human reproduction (Oxford, England) · Free full text on PubMed Central

What proportion of fertilized human ova are lost before implantation? An estimated 40 to 50% of fertilized ova fail to implant. Preimplantation loss is not detectable with current technology. Published estimates of preimplantation loss range from 10 to 70%. STUDY DESIGN, SIZE, We combine data from epidemiologic, demographic, laboratory and in vitro fertilization studies to construct an empirical framework for the estimation of preimplantation loss. This framework is summarized in a user-friendly Excel file included in supplement. PARTICIPANTS/MATERIALS, SETTING, We draw from multiple sources to generate plausible estimates of fecundability, sterility, transient anovulation, intercourse patterns and the proportion of ova fertilized in the presence of sperm. We combine these estimates to generate a summary estimate of preimplantation loss. This estimate can be considered an average for couples in their prime reproductive years. MAIN Under a plausible range of assumptions, we estimate that 40 to 50% of fertilized ova fail to implant. LIMITATIONS, A crucial factor in estimating preimplantation loss is the probability that an ovum will be fertilized when exposed to sperm. Human data are available only from in vitro fertilization (IVF), which may not accurately represent events in vivo. We therefore assume a range of in vivo fertilization rates, from 64% (human IVF data) to 90% (mouse data). Our estimate of preimplantation loss takes into account the biological processes relevant to fertilization and loss. Using this empirical basis for estimation, we find support for the usual assumption that risk of loss is highest in the earliest days following fertilization. Furthermore, this framework can provide improved estimates as better reproductive data become available. To the extent that our estimates are accurate, more fertilized ova are apparently lost in vitro than in vivo, suggesting that further improvements in IVF success rates may be possible. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Intramural Program of the National Institute of Environmental Health Sciences, NIH. Professor Adashi serves as Co-Chair of the Safety Advisory Board of Ohana Biosciences, Inc. The other authors have no competing interests. N/A.

Clomiphene Citrate – Initiated Ovulation: The State of the Art. In: Wallach EE, Zacur HA (Eds). Reproductive Medicine and Surgery

Adashi EY, 1995 · Mosby

Ovulation induction

Kennedy JL et al., 1987 · Obstet Gynecol Clin North Am

Methods to induce ovulation in anovulatory women have blossomed over the last three decades. The introduction of clomiphene citrate in 1960 allowed us for the first time to provoke follicle development in patients with normo or hyperestrogenic forms of anovulation. The development of human menopausal gonadotropins in the early 1960s gave us a much more powerful tool with which to influence ovulation in all forms of ovulatory disturbances. Elucidation of the pulsatile secretion of gonadotropin-releasing hormone together with its isolation and synthesis has allowed us to streamline our methods of inducing ovulation in hypothalamic amenorrheic patients by using endogenous control mechanisms to maximize both safety and effectiveness. However, there are problems yet to solve. Polycystic ovarian disease has long eluded our efforts to resolve its pathophysiology as well as to devise a consistently effective and safe means of treatment. Methods to restore ovulation in patients with polycystic ovarian disease refractory to clomiphene citrate is the quest of future investigations.

Fertility following bilateral ovarian wedge resection: a critical analysis of 90 consecutive cases of the polycystic ovary syndrome

Adashi EY et al., 1981 · Fertil Steril

Fertility following bilateral ovarian wedge resection (BOWR) was evaluated in a retrospective cohort study of 90 consecutive cases of the polycystic ovary syndrome. Post-BOWR follow-up was available for varying time spans of up to 10 years. BOWR resulted in the resumption of menstrual cyclicity in 91.1% (82/90) of the cases. However, within this ovulatory group, 26 patients were characterized by oligo-ovulation and a significantly reduced conception rate (29.2%), as compared with that of 56 normo-ovulatory counterparts (60.3%). Although the crude overall conception rate for this series was 47.8%, the overall cumulative probability of conception at the end of follow-up as determined by life table analysis was 73%. The likelihood of conception at any given point in time was estimated by a monthly fecundability rate of 1.34%. Our findings also indicate that the probability of post-BOWR conception was unaffected by age, race, ward status, or duration of infertility. In contrast, persistent post-BOWR oligo- or anovulation and the presence of concurrent tuboperitoneal disease were reaffirmed as the most important determinants of the likelihood of post-BOWR conception. A minimum incidence of 7.8% was documented for acquired post-BOWR pelvic disease.

Clomiphene citrate therapy for luteal phase defect

Downs KA et al., 1983 · Fertil Steril

The incidence of luteal phase defects in 366 infertility patients was 12.7%. Life-table analysis was used for determination of the conception rate with clomiphene citrate therapy, and with this method, evidence was found for the presence of two subgroups with respect to response. The crude conception rate was 40.9%. In a group of patients with a luteal phase defect and no other infertility factors, those that conceived had a significantly larger mean biopsy delay than those who did not (6.28 days versus 4.32; P less than 0.02). In a group with a histologic delay of 5 days or more, the conception rate was 79%, while the rate was only 8.9% in those with a less severe deficit (P less than 0.001). Theoretic considerations for clomiphene citrate therapy are discussed.

Efficacy of oral micronized progesterone in the treatment of luteal phase defects

Frishman GN et al., 1995 · J Reprod Med

Vaginal progesterone suppositories are an accepted treatment for infertility attributed to luteal phase defects. Although oral micronized progesterone may be preferable to suppositories for many patients, there are no studies on its use for patients with luteal phase defects. This study evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects. Seven women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg by mouth three times a day). Endometrial biopsies were performed to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation. On oral micronized progesterone, all patients had in-phase endometrial biopsies. Despite complaints of drowsiness, the majority of patients preferred the oral formulation over the vaginal route of administration. We conclude that oral micronized progesterone is efficacious in the treatment of luteal phase defects.

The luteal phase defect: the relative frequency of, and encouraging response to, treatment with vaginal progesterone

Rosenberg SM et al., 1980 · Fertil Steril

Three hundred and ninety-six patients were evaluated for primary and secondary infertility between December 1976 and May 1979 at a large referral center. Timed late luteal endometrial biopsies were routinely obtained as part of the work-up and were repeated for confirmation if subsequent menses did not occur within 2 days of the expected date. If both biopsies were abnormal, a diagnosis of luteal phase defect (LPD) was made and patients were treated with vaginal progesterone suppositories for a minimum of 6 months. LPD was discovered in 32 of 396 patients (8.1%); among those patients whose infertility was not complicated by other abnormalities, 9 of 13 conceived (70%) and 7 of 13 carried to term (54%). These data suggest an incidence higher than generally recognized and a very encouraging response to replacement therapy.

Clomiphene citrate therapy of infertile women with low luteal phase progesterone levels

Hammond MG et al., 1982 · Obstet Gynecol

Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.