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Andrology Mar 2022Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first-choice therapy, with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first-choice therapy, with several side effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism.
METHODS
The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects.
RESULTS
We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.
CONCLUSION
Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects.
Topics: Clomiphene; Follicle Stimulating Hormone; Humans; Hypogonadism; Luteinizing Hormone; Male; Testosterone
PubMed: 34933414
DOI: 10.1111/andr.13146 -
JAMA Jun 2017Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence.
OBJECTIVE
To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups.
INTERVENTIONS
Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity.
MAIN OUTCOMES AND MEASURES
The primary outcome was live birth. Secondary outcomes included adverse events.
RESULTS
Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%).
CONCLUSIONS AND RELEVANCE
Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01573858.
Topics: Acupuncture Therapy; Adult; Body Mass Index; Clomiphene; Combined Modality Therapy; Contusions; Diarrhea; Double-Blind Method; Drug Administration Schedule; Female; Fertility Agents, Female; Humans; Infertility, Female; Live Birth; Polycystic Ovary Syndrome; Pregnancy; Single-Blind Method; Time Factors
PubMed: 28655015
DOI: 10.1001/jama.2017.7217 -
The New England Journal of Medicine Jul 2014Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.
METHODS
In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period.
RESULTS
Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.
CONCLUSIONS
As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
Topics: Adult; Clomiphene; Double-Blind Method; Female; Fertility Agents, Female; Humans; Infertility, Female; Kaplan-Meier Estimate; Letrozole; Live Birth; Luteal Phase; Male; Nitriles; Ovulation; Polycystic Ovary Syndrome; Pregnancy; Quality of Life; Triazoles
PubMed: 25006718
DOI: 10.1056/NEJMoa1313517 -
Fertility and Sterility Feb 2020To provide evidence-based recommendations to practicing physicians and others regarding the effectiveness and safety of therapies for unexplained infertility.
OBJECTIVE
To provide evidence-based recommendations to practicing physicians and others regarding the effectiveness and safety of therapies for unexplained infertility.
METHODS
ASRM conducted a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1968 through 2019. The ASRM Practice Committee and a task force of experts used available evidence and informal consensus to develop evidence-based guideline recommendations.
MAIN OUTCOME MEASURE(S)
Outcomes of interest included: live-birth rate, clinical pregnancy rate, implantation rate, fertilization rate, multiple pregnancy rate, dose of treatment, rate of ovarian hyperstimulation, abortion rate, and ectopic pregnancy rate.
RESULT(S)
The literature search identified 88 relevant studies to inform the evidence base for this guideline.
RECOMMENDATION(S)
Evidence-based recommendations were developed for the following treatments for couples with unexplained infertility: natural cycle with intrauterine insemination (IUI); clomiphene citrate with intercourse; aromatase inhibitors with intercourse; gonadotropins with intercourse; clomiphene citrate with IUI; aromatase inhibitors with IUI; combination of clomiphene citrate or letrozole and gonadotropins (low dose and conventional dose) with IUI; low-dose gonadotropins with IUI; conventional-dose gonadotropins with IUI; timing of IUI; and in vitro fertilization and treatment paradigms.
CONCLUSION(S)
The treatment of unexplained infertility is by necessity empiric. For most couples, the best initial therapy is a course (typically 3 or 4 cycles) of ovarian stimulation with oral medications and intrauterine insemination (OS-IUI) followed by in vitro fertilization for those unsuccessful with OS-IUI treatments.
Topics: Aromatase Inhibitors; Clomiphene; Evidence-Based Practice; Female; Fertilization in Vitro; Gonadotropins; Humans; Infertility, Female; Insemination, Artificial; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 32106976
DOI: 10.1016/j.fertnstert.2019.10.014 -
Endocrinology, Diabetes & Metabolism May 2023Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first-choice treatment for male hypogonadism,...
BACKGROUND
Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first-choice treatment for male hypogonadism, with several side effects, that is, subfertility. Clomiphene citrate (CC) is an alternative off-label therapy for a certain group of hypogonadal males, especially for those with an active or future child wish. There is scarce literature in usage of CC for men with hypogonadism. The aim of this retrospective study was to evaluate the effectiveness and safety of CC for hypogonadal males.
METHODS
In this single-centre study, men treated with CC for hypogonadism were evaluated retrospectively. Primary outcome was hormonal evaluation including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Secondary outcomes were hypogonadal symptoms, metabolic and lipid parameters, haemoglobin (Hb), haematocrit (Ht), prostate specific antigen (PSA), side effects, the effect of a trial without medication and potential predictors for biochemical and clinical response.
RESULTS
In total, 153 hypogonadal men were treated with CC. Mean TT, FT, LH and FSH increased during treatment. TT increased from 9 to 16 nmol/L, with a biochemical increase in 89% of the patients. In patients who continued CC treatment, an increased level of TT persisted after 8 years of treatment. With CC treatment, 74% of the patients experienced hypogonadal symptom improvement. LH at the lower normal range before CC treatment was predictive for better TT response. During CC therapy, few side effects were reported and no clinical important changes in PSA, Hb and Ht were found.
CONCLUSION
Clomiphene citrate is an effective therapy on short and long term, improving both clinical symptoms and biochemical markers of male hypogonadism with few side effects and good safety aspects.
Topics: Child; Humans; Male; Testosterone; Retrospective Studies; Prostate-Specific Antigen; Clomiphene; Hypogonadism; Luteinizing Hormone; Follicle Stimulating Hormone
PubMed: 36998229
DOI: 10.1002/edm2.416 -
Ugeskrift For Laeger Oct 2023This review describes the current evidence regarding the putative indications of letrozole (LTZ) in fertility treatment. Prior to intrauterine insemination, LTZ is... (Review)
Review
This review describes the current evidence regarding the putative indications of letrozole (LTZ) in fertility treatment. Prior to intrauterine insemination, LTZ is recommended in women with normogonadotrophic oligo-anovulation. In ovulatory women, LTZ is equal to clomiphene and may be used instead of exogenous gonadotrophin. LTZ may be used as co-treatment in poor responders prior to in vitro fertilization/intracytoplasmic sperm injection. In addition, LTZ prior to frozen-thawed embryo transfer is increasingly used in women with normogonadotrophic oligo-anovulation.
Topics: Male; Female; Humans; Letrozole; Anovulation; Fertility Agents, Female; Semen; Clomiphene
PubMed: 37873987
DOI: No ID Found -
Fertility and Sterility Apr 2022Growth hormone, letrozole, and clomiphene citrate do not have US Food and Drug Administration approval for their use in in vitro fertilization (IVF) cycles. However,... (Review)
Review
Growth hormone, letrozole, and clomiphene citrate do not have US Food and Drug Administration approval for their use in in vitro fertilization (IVF) cycles. However, despite this fact, they often are used to augment the IVF cycle in women considered "low responders." Unfortunately, because of the problems inherent to recruiting women who have undergone several unsuccessful IVF treatment cycles, and their inevitable low live birth rate, studies involving adjuvants for women considered low responders to ovarian stimulation often are underpowered. This is compounded further by the difficulty in recruiting vulnerable women to a study with a placebo arm. Consequently, the evidence base for their use as adjuncts to IVF treatment may be limited, and consequently their use may be empirical rather than evidence based. This short narrative review describes the evidence for these "add-ons" for a patient with a low response to ovarian stimulation. It suggests that a woman with a low ovarian response will derive benefit from using growth hormone; with a reduction in the ovarian stimulation required for oocyte retrieval, collection of a greater number of oocytes, and improvement in the clinical pregnancy rate. Although there currently is insufficient evidence to state categorically that it leads to an increased chance of a live birth. In the same situation, clomiphene citrate and letrozole lead to a reduced requirement for gonadotropins before oocyte retrieval, but with no improvement in live birth rate for their use.
Topics: Clomiphene; Female; Fertilization in Vitro; Humans; Live Birth; Ovulation Induction; Pregnancy; Pregnancy Rate; Sperm Injections, Intracytoplasmic
PubMed: 35256192
DOI: 10.1016/j.fertnstert.2022.01.027 -
Journal of Medicine and Life May 2023Polycystic ovary syndrome (PCOS) is characterized by menstrual irregularities, high androgen levels, and ovarian cysts. Clomiphene citrate (Clomid) and letrozole have... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing efficacy and safety of stair step protocols for clomiphene citrate and letrozole in ovulation induction for women with polycystic ovary syndrome (PCOS): a randomized controlled clinical trial.
Polycystic ovary syndrome (PCOS) is characterized by menstrual irregularities, high androgen levels, and ovarian cysts. Clomiphene citrate (Clomid) and letrozole have both been investigated as ovulation induction therapies for PCOS. This interventional study aimed to compare the efficacy and safety of a stairstep practice of letrozole versus clomiphene citrate in women with PCOS. A total of 100 women diagnosed with PCOS and infertility participated in the study, which took place from March 2021 to July 2022 at the Maternity and Children Teaching Hospital in Adiwaniyah Province, Iraq. Participants were randomly assigned to one of two groups (each with 50 women): the first group received clomiphene citrate in a stair step pattern (single dose of 50 mg, 100 mg, and 150 mg) for five days, for a maximum of three cycles; the second group received letrozole in a stair step pattern (single dose of 2.5, 5, and 7.5 mg) for five days, for a maximum of three cycles. Follicle size was monitored using ultrasound to achieve a follicle size >18 mm. The ovulation rate was higher in the letrozole group (86.0%) compared to the clomiphene citrate group (72.0%), although the difference was not statistically significant (p=0.086). The pregnancy rate was slightly higher in the letrozole group (22.0% 18.0%), but also not statistically significant (p=0.617). However, the mean time from menstruation to ovulation was significantly shorter in the letrozole group (17.20±1.32 days) compared to the clomiphene citrate group (24.08 ± 1.56 days, p<0.001). There were no significant differences in common side effects between the two groups. Overall, letrozole was found to be as safe as clomiphene citrate but demonstrated a shorter time to ovulation. Further studies with larger sample sizes are necessary to validate these findings and determine their clinical implications.
Topics: Child; Female; Humans; Pregnancy; Clomiphene; Fertility Agents, Female; Infertility, Female; Letrozole; Nitriles; Ovulation Induction; Polycystic Ovary Syndrome; Triazoles
PubMed: 37520487
DOI: 10.25122/jml-2023-0069 -
BMJ Clinical Evidence Nov 2010About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm... (Review)
Review
INTRODUCTION
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count. In developed countries, 80% to 90% of couples attempting to conceive are successful after 1 year and 95% after 2 years.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for infertility caused by ovulation disorders? What are the effects of treatments for tubal infertility? What are the effects of treatments for infertility associated with endometriosis? What are the effects of treatments for unexplained infertility? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 55 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clomifene; drug-induced ovarian suppression; gonadotrophin priming of oocytes before in vitro maturation; gonadotrophins; gonadotrophin-releasing hormone agonists plus gonadotrophins; gonadotrophin-releasing hormone antagonists; in vitro fertilisation; intrauterine insemination alone, or combined with gonadotrophins or clomifene; laparoscopic ablation of endometrial deposits; laparoscopic ovarian drilling; laparoscopic removal; metformin; ovarian wedge biopsy; pulsatile gonadotrophin-releasing hormone; selective salpingography plus tubal catheterisation; tamoxifen; tubal flushing; and tubal surgery before in vitro fertilisation.
Topics: Administration, Oral; Anovulation; Clomiphene; Female; Humans; Infertility; Infertility, Female; Ovulation Induction; Polycystic Ovary Syndrome
PubMed: 21406133
DOI: No ID Found -
PloS One 2022Over the last decade, we've observed an enormous social media development, which have recently become commercial services. Hence, we aimed to verify if Facebook might be...
Over the last decade, we've observed an enormous social media development, which have recently become commercial services. Hence, we aimed to verify if Facebook might be considered as a source of access to medicines. We also intended to identify prescription (Rx) and over the counter (OTC) medicines if available on that platform. The study was conducted from January 2019 to July 2020. We investigated offers of pharmaceuticals posted on Facebook (individual posts and communities) between 2016 and 2019. Medicines were divided into Rx and OTC brands and in accordance with their possible therapeutic use. We verified whether the medicines were for sale, to exchange, or available for free. Posts and groups were investigated for example, by entering the phrase "for free," followed by a city in Poland. Out of 409 offers, 380 (92.91%) concerned Rx brands and 29 (7.09%) OTC brands. 315 (77.02%) medications were available "for free". In 47 (11.49%) cases, an "exchange" was expected, and 47 (11.49%) announcements were marked as "for sale". Cardiovascular medicines (n = 125; 30.56%) were the most popular. There were also antidiabetics (n = 38; 9.29%) and antipsychotics (n = 28; 6.84%). We also found clear candidates for misuse. These were opioids (n = 7; 1.71%), benzodiazepines (n = 2; 0.48%), clomifene (n = 1; 0.24%), and letrozole (n = 1; 0.24%). Facebook provides the possibility of uncontrolled access to medicines. The majority of offers concerned Rx brands, including opioids and benzodiazepines. Medicines offered on Facebook were mainly accessible for free. The scope and the number of medications offered on Facebook should make this issue a hazardous phenomenon.
Topics: Benzodiazepines; Clomiphene; Humans; Hypoglycemic Agents; Letrozole; Nonprescription Drugs; Social Media
PubMed: 36227918
DOI: 10.1371/journal.pone.0275272