Usefulness of Newly Devised Clomiphene Citrate Administration Method Compared with the Conventional Method in Ovulation and Pregnancy

Objective: Since not all women wish to conceive a child through aggressive treatment, we investigated the usefulness of modified repeated intracyclic clomiphene citrate (CC) therapy (repeated CC therapy) as a newly devised administration method. Methods: We evaluated the effects of CC administration on menstrual cycle length and retrospectively compared ovulation and pregnancy in 220 women who received CC at our hospital. Patients in the conventional method group received 50 mg per day for five days, starting on the fifth day of menstruation (withdrawal bleeding). Groups with and without menstrual cycle shortening after conventional CC administration were compared. The repeated CC therapy group was also compared with the non-shortened group. Repeated CC therapy was administered for the first five days as in the conventional method, and a second five-day repeat treatment was administered after an interval of five to seven days. Pregnancy rates, including indirect pregnancies, were evaluated by three different methods. Results: Ovulation and pregnancy rates were significantly better in the shortened group than in the non-shortened group (P < 0.001 and P = 0.010, respectively). Even in the non-shortened group, ovulation and pregnancy rates including indirect pregnancies were significantly improved when ovulation was observed with repeated CC therapy (P < 0.001 and P = 0.022, respectively). Conclusions: For patients whose menstrual cycle was not improved or shortened, repeated CC therapy as the newly devised CC administration method is useful as the next step after the conventional CC administration method.

The advantage of low-dose clomiphene citrate for overweight women with anovulation

Background:To investigate the potential advantage of using low-dose clomiphene citrate to promote ovulation in women with overweight or obesity.Methods:The patients with overweight were divided randomly into regular clomiphene citrate group(clomiphene citrate 50 mg/d,n=83)and low-dose clomiphene citrate group(clomiphene citrate 25 mg/d,n=105).All patients received treatment from the 5th day of their menstrual cycles.Results:Luteinizing hormone levels and estradiol levels were more increased in the low-dose group compared with the regular group(P<0.05).Low-dose group showed significantly thicker endometrium,fewer dosage and shorter days of human menopausal gonadotropin,less numbers of mature follicles and lower rates of cancellation(P<0.05)on human chorionic gonadotropin day.After human chorionic gonadotropin injection,the ovulation rate in the low-dose group was significantly higher than the regular group(P<0.05).No difference was detected in the biochemical pregnancy rates both groups(P>0.05).Conclusion:The low-dose clomiphene citrate treatment significantly reduced the number of mature follicles and increased the thickness of endometrium on the human chorionic gonadotropin day with less side effects.The low-dose clomiphene citrate also achieved the better ovulation rate.

Study of Combined Use of Clomiphene Citrate and Gonadotropins on the Infertile Patients with PCOS

Objective To investigate the efficacy and safety of combined use of clomiphene citrate （CC） and gonadotropins （Gn） on the infertile patients with PCOS. Methods A total of 367 infertile patients with PCOS were included in this retrospective study. Patients received CC from menstrual cycle day 3 until the day of triggering and human menopausal gonadotrophins （hMG） from menstrual cycle day 5 until the ovulation day. Gn duration and doses, serum LH and estradiol levels, transferable embryos, incidence of OHSS, frozen-thawed embryo implantation and clinical pregnancy rates were compared among CC plus hMG, long and short protocols. Results Gn duration and doses, blood estrogen level transferable embryos and incidence of OHSS in the group of CC plus hMG were decreased significantly than those of long and short protocols. No differences were observed in the frozen-thawed embryo implantation and clinical pregnancy rates among three groups. Conclusion Mild stimulation of CC combined with hMG on infertile patients with high risk for OHSS is safe and efficient.

Clomiphene Citrate as An Adjuvant to hMG Stimulation of the Ovaries in Mid-to-late Follicular Phase and Subsequently Pregnancy Outcome of Frozen-thawed Embryo Transfers

Objective To compare the results of a novel regimen of human menopausal gonadotrophin （hMG） in combination with clomiphene citrate （CC） in mid-to-late follicular phase with those of a short protocol of GnRH agonist （GnRHa） and hMG used for IVF. Methods In the retrospective study, 842 patients undergoing IVF were collected and classified into two groups： hMG in combination with CC in mid-to-late follicular phase （group A, n=319） and short protocol of GnRHa-hMG （group B, n=523）. The main outcome measures were ovarian responses in stimulation cycles and pregnancy outcomes in subsequent frozen-thawed embryo transfer （FET） cycles. Results In group A, the serum LH concentration on day 8 -10 was similar with that on the day of hCG administration （2.43 ± 1.92 IU vs 2.51 ±2.05 IU）. The number of mature follicles and oocytes retrieved was significantly lower in group A than in group B while the fertilization rate and the cleavage rate were comparable. The clinical pregnancy rate （47. 79% vs 48.04%）, the implantation rate （32.49% vs 33.11%） and the cumulative pregnancy rate （58.09% vs 60.22%） were respectively similar in group A and group B. Conclusion hMG in combination with CC in mid-to-late follicular phase results in the same pregnancy outcome as short protocol. The novel protocol may take the advantage of eliminating the occurrehce of a premature endogenous LH Surge.

Clomiphene Citrate or Medroxyprogesterone Acetate with Human Menopausal Gonadotropin in Poor Responders during In vitro Fertilization/Intracytoplasmic Sperm Injection Treatments Combined with Embryo Cryopreservation?

Objective:This study aimed to compare the efficacy of clomiphene citrate(CC)with human menopausal gonadotropin(hMG)and that of medroxyprogesterone acetate(MPA)with hMG in poor responders defined according to the Bologna criteria.Methods:The data of patients with poor ovarian response(POR)according to the Bologna criteria from September 2016 to November 2017 were retrospectively reviewed.All participants received either CC+hMG or the progesterone-primed ovarian stimulation protocol(PPOS)protocol.Results:A total of 340 patients and 563 in vitro fertilization cycles were analyzed in this study.The incidence of spontaneous luteinizing hormone(LH)surge and the mean LH level on trigger day were significantly lower in the PPOS group than in the CC+HMG group(0.04%vs.3.49%and 4.26±3.59 vs.9.38±6.92 mIU/mL,respectively,P<0.05);however,the incidence of premature ovulation was similar between the two groups.The number of viable embryos harvested was not statistically different between the two groups(1.7±1.1 vs.1.5±0.8,P=0.06).The mean dose and duration of hMG were significantly higher in the PPOS group than in the CC+hMG group(908.7±556.6 vs.177.9±214.5 IU and 6.0±3.4 vs.1.2±1.5 days,respectively,P<0.05).However,the number of oocytes retrieved,number of metaphase II oocytes,and fertilization rate were comparable between the two groups.Conclusions:The CC with low-dose gonadotropin strategy was superior to the MPA with hMG protocol for POR.

Effects of the Interval between Ovulation Induction using Clomiphene Citrate and Frozen Embryo Transfer on Pregnancy Outcome

Objective:To explore the best timing for frozen embryo transfer(FET)after ovarian stimulation and egg retrieval using the clomiphene citrate(CC)+human menopausal gonadotropin(hMG)ovulation induction regimen through a retrospective analysis.Methods:Data of patients who underwent CC+hMG ovulation induction and FET from January 2014 to December 2019 were analyzed retrospectively.The patients were divided into three groups according to the interval from egg retrieval to FET:CC1(within 1 menstrual cycle),CC2(2 menstrual cycles),and CC3(≥3 menstrual cycles).Indicators such as hormone levels and pregnancy outcomes were recorded to explore the effect of different intervals on pregnancy outcome.Results:A total of 1,082 transfer cycles were included in this retrospective analysis.The implantation,clinical pregnancy,and live birth rates in the CC1 group were significantly lower than those in the CC2 and CC3 groups(P<0.05).The E2/P4 ratio on progesterone injection day(3 days before thawed embryo transfer)was lower in the CC1 group than in the other groups(P<0.05).After adjusting for all factors using multifactor regression analysis,the interval between egg retrieval and FET was found to be an independent predictor of the implantation,pregnancy,and live birth rates.Conclusion:An interval of more than one menstrual cycle between the day of egg retrieval after ovarian stimulation with the CC+hMG ovulation induction regimen and the day of FET can result in high implantation,clinical pregnancy,and live birth rates,which can lead to an improved pregnancy outcome.

A novel herbal combination ameliorates ovarian dysfunction and regulates altered biochemical parameters in rats with letrozole-induced polycystic ovary syndrome

Objective:To investigate the potential activity of novel herbal combination and novel herbal formulation(syrup)in female Sprague Dawley rats with letrozole-induced polycystic ovary syndrome(PCOS).Methods:Forty-two rats were randomly divided into seven groups with six rats in each group.Group 1 received 0.5%carboxy methylcellulose orally for 37 days and served as the normal control group.Group 2 was orally administered with letrozole of 1 mg/kg for 21 days and served as the PCOS induction group without treatment.Group 3 to 7 were administered with letrozole of 1 mg/kg for 21 days orally to induce PCOS,and then respectively received clomiphene citrate at 1 mg/kg,100 and 200 mg/kg of novel herbal combination,200 mg/kg of novel herbal formulation(syrup),and 400 mg/kg of marketed formulation of Pushyanuga churna,once daily for 15 days.Effects of the novel herbal combination and its syrup formulation were evaluated on the hormonal profile,the levels of antioxidants,the lipid profile and on the ovarian morphology,using letrozole-induced PCOS model in rats.Results:Letrozole caused alterations in hormonal levels and lipid levels similar to PCOS and ovarian histology showed presence of ovarian cysts confirming the induction of PCOS in rats.On treatment with the novel herbal combination and its syrup formulation in PCOS-induced rats,the altered hormonal and lipid profiles showed significant recovery to normal levels.Ovarian histology confirmed the restoration of folliculogenesis in the PCOS-induced rats.The treatment with the syrup formulation of novel herbal combination was found to be more effective than novel herbal combination and showed better recovery in various parameters evaluated.The results of the study,however,suggested that treatment with novel herbal combination and its syrup formulation provided minimal protection against oxidative stress caused due to the induction of PCOS.Conclusions:The integrated approach for management of PCOS is to counterbalance the limitations associated with modern therapy.Both the novel herbal combination and the syrup formulation of novel herbal combination show efficacy in the management of PCOS in rats and restore folliculogenesis in the ovary.The syrup formulation of novel herbal combination is most effective in the management of PCOS and shows potential to be developed as an adjuvant therapeutic agent.

Intrauterine Insemination—Our Results between the Years 2008-2012

The purpose of this retrospective study was to determine whether or not there was a significant relationship between women’s age as a cause of sterility and pregnancy after IUI. Furthermore, we evaluated the effect of stimulation of antiestrogens and time of hCG administration on the success of IUI in relation to the age of women. During the period between 2008 and 2012, we performed a total number of 793 IUI. Patients were prepared for IUI in the natural cycle and stimulation with antiestrogens (clomiphene citrate-CC). Ovulation was induced by hCG (Ovitrelle) 40 hours before IUI or immediately after the procedure. Sperm was processed through density gradients. The average success rate of IUI was 10.2% of pregnant women per cycle. Significantly the highest number of pregnant women 16.3% was women with a diagnosis of anovulation. Significantly the lowest success rate of IUI was at the immunological cause of infertility and endometriosis. There was no evidence of age dependence for women on the success of IUI. Stimulation of CC did not significantly increase the chance of becoming pregnant. There was also no statistically significant difference in hCG before and after IUI pregnancy success. The most important group of women for whom IUI is a suitable form of assisted reproduction consists of patients of 35 years old with anovulation cause of sterility. Those patients with an immunological cause of infertility and endometriosis have significantly lower chances of conceiving after IUI and it is preferable for them to choose other techniques of assisted reproduction and embryo transfer.

Which is the Best Protocol of Ovarian Stimulation Prior to Artificial Insemination by Donor

Objective To compare the different ovarian stimulation protocols, clomiphene citrate （CC）, letrozole, human menopausal gonadotropin （hMG） only or combined with CC or letrozole in women undergoing artificial insemination by donor （AID）. Methods In this prospective clinical trial, 671 couples prepared for AID cycles were randomly allocated to 6 groups according to receive different protocols for the first time, natural cycle （group A, n=l14）, CC （group B, n=lOl）, CC and hMG （group C, n=124）, letrozole （group D, n=97）, letrozole and hMG （group E, n=123） and hMG only （group F, n=l12）. Outcomes including total dose of hMG, duration of hMG therapy, dominant follicles number, endometrial thickness, rates of clinical pregnancy, miscarriage, ovarian hyperstimulation syndrome （OHSS）, multiple pregnancy and can- celation were compared among the 6 groups. Results The total doses and duration of administered hMG were significantly lower in group C and group E than in group F. Dominant follicle number was significantly less in group A and more in group C than in other groups. Endometrial thickness of group B was significantly lower than that of other groups. Clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, OHSS rate and cancelation rate were not statistically different among the stimulation groups. Conclusion AID cycles in which both CC and letrozole had been administered may require shorter duration and a lower total gonadotropin dose, while the clinical out-comes were similar.

Alternatives to testosterone replacement： testosterone restoration

The European Male Aging Study has demonstrated that the hypogonadism of male aging is predominantly secondary. Theoretically with appropriate stimulation from the pituitary, the aging testis should be able to produce eugonadal levels of testosterone. The strategies for the treatment of late onset hypogonadism （LOH） have focused on replacement with exogenous testosterone versus restoration of endogenous production. The purpose of this article is to review existing peer-reviewed literature supporting the concept of restoration of endogenous testosterone in the treatment of LOH.

Anti-androgenic effect of Symplocos racemosa Roxb.against letrozole induced polycystic ovary using rat model

Objective:To investigate the anti-androgenic properties of Symplocos racemosa Roxb.(S.racemosa)in the treatment of hyperandrogenemia associated polycystic ovary syndrome(PCOS)in a letrozole induced PCOS rat model.Methods:The testosterone levels were used to evaluate the anti-androgenic effect of S.racemosa in letrozole induced PCOS rats for 21 d.The low(250 mg/kg),mid(500 mg/kg)and high dose(1000 mg/kg)of S.racemosa was given to the PCOS induced rats for 15 d post letrozole induction to determine the effective dose of S.racemosa in the treatment of hyperandrogenemia associated PCOS.The hormones such as estrogen and progesterone were also assayed along with testosterone to determine the fluctuations in sex steroid levels in PCOS rats induced by letrozole.Results:S.racemosa treatment significantly decreased testosterone levels which were found to be elevated in PCOS rats induced by letrozole.S.racemosa significantly restored other blood biochemical parameters such as estrogen,progesterone and cholesterol levels.It also restored the histology of ovarian tissue.The ovarian weights and uterine weights were also significantly recovered after the S.racemosa treatment.Conclusions:The mid dose(500 mg/kg)and high dose(1000 mg/kg)of S.racemosa were found to be effective in the treatment of hyperandrogenemia in PCOS.This effect of S.racemosa was found to be comparable with clomiphene citrate.Clomiphene citrate which was being used as the major medicine in the treatment of PCOS could now be replaced with S.racemosa in the management of PCOS.