Oral anti-estrogen and medical adjuncts for subfertility associated with anovulation. Cochrane Database Syst Rev. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril.
A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins. Comparison of letrozole with continuous gonadotropins and clomiphene-gonadotropin combination for ovulation induction in PCOS women after clomiphene citrate failure: a randomized prospective clinical trial.
J Assist Reprod Genet. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod. Comparison of tamoxifen and clomiphene citratefor ovulation induction: a meta-analysis. Messinis IE. Ovulation induction: a mini review.
A comparison of letrozole to gonadotropins for ovulation induction, in subjects who failed to conceive with clomiphene citrate. Letrozole vs clomiphene citrate in patients with ovulatory infertility. A randomized trial of superovulation with two different doses of letrozole.
Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum ReprodUpdate. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility.
Letrozole versus combined metformin and clomiphene citrate for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial. A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation.
Am J Obstet Gynecol. Wu Ch. Less miscarriage in pregnancy following Tamoxifen treatment of infertile patients with luteal phase dysfunction as compared to clomiphene treatment. Early Pregnancy. Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstetricia et Gynecologica. Aromatase inhibitors: possible future applications.
Acta Obstet Gynecol Scand. Support Center Support Center. External link. Overweight women respond less well Polson et al. It is frustrating that the restoration of ovulation by CC does not produce a much higher pregnancy rate. In our experience, the prevalence of endometrial suppression is one in every 6—7 patients and, if noted in the first cycle of treatment with CC, it will almost certainly be seen in repeated cycles in the same woman. There is little point in persisting after even one cycle, and a step-up to other forms of ovulation induction is recommended.
We have demonstrated that pre-treatment with micronized progesterone is capable of modulating LH pulsatility, reducing LH concentrations and inducing a more favourable environment for ovulation induction with CC Homburg et al.
This treatment initiated a response to CC and yielded consequent pregnancies in previous non-responders to CC. A course of six ovulatory cycles is usually sufficient to know whether pregnancy will be achieved using CC before moving on to more complex treatment as it has been reported that 71— CC blocks the negative feedback mechanism which the eventually rising estradiol levels would normally invoke to reduce discharge of FSH.
The continued flow of FSH encourages multiple follicle development which is relatively common. Although a very controversial issue due to a lack of evidence for a direct causal relationship, several investigators have found in retrospective studies that an increased prevalence of miscarriage is associated with high serum LH concentrations in the mid-follicular phase Homburg et al.
The increased prevalence of miscarriage following CC therapy may, in part, be due to the high LH values induced immediately after this treatment. Kousta et al. The prevalence of congenital abnormalities following CC treatment is no different from those seen in spontaneously conceived pregnancies Correy et al. Unpleasant side effects of CC are few and far between, although some women will complain of hot flushes and some of nausea.
CC is, however, usually very well tolerated. While mild ovarian enlargement is relatively common, in almost 40 years of practice, I have never seen a full blown ovarian hyperstimulation syndrome OHSS as a result of CC treatment. Occasional cyst formation can be treated conservatively.
CC is often given without any observation of the events of the cycle. However, monitoring of the CC-treated cycle by ultrasound evaluation of follicular growth and endometrial thickness on days 12—14 of the cycle is justified by the identification of those who are not responding or have depressed endometrial thickness, and is helpful in the timing of natural intercourse or IUI.
Confirmation, or otherwise, of ovulation can be obtained with estimation of the progesterone concentration in the assumed mid-luteal phase which is preferable to a basal body temperature chart. The added expense of careful monitoring is neutralized by the prevention of protracted periods of possibly ineffective therapy and delay in the inception of more efficient treatment.
In order to improve the outcome of treatment with CC, several adjuvants to CC treatment have been suggested. The addition of dexamethazone as an adjunct to CC therapy in a dose of 0. However, glucocorticoid steroid therapy often induces side effects including increased appetite and weight gain, and should probably be reserved for women who have congenital adrenal hyperplasia as a cause for their anovulation.
CC has also been employed for ovarian stimulation in ovulating women, mainly for idiopathic unexplained infertility and often combined with IUI. The rationale is presumably that CC overcomes a subtle defect in ovulatory function or increases the number of mature follicles so increasing the likelihood of pregnancy Guzick et al.
Here the success rate has been, understandably, notably less than in anovulatory women. In a collection of data on the efficacy of treatment for unexplained infertility, the use of CC alone produced a pregnancy rate of 5.
While this is significantly superior to timed intercourse alone, it should be remembered that the baseline level from merely expectant treatment in these cases ranges from 1. In IVF, co-treatment with CC and gonadotrophins has enjoyed brief periods of popularity as an attempt to decrease costs of medications.
However, this co-treatment never seemed to achieve the same results as the more favoured protocols of today, and this combination is rarely used now. Three possible contenders have emerged as the replacement of CC as primary, first-line treatment for oligo- or anovulation and WHO group II infertility: i metformin; ii aromatase inhibitors; and iii recombinant FSH.
Insulin is of prime importance in the pathophysiology of PCOS. Weight loss in the obese is a very effective way of achieving this, but weight loss and lifestyle change often seem to be insurmountable objects for the obese patient with PCOS and are not applicable for lean patients.
The alternative possibility of using insulin-lowering drugs particularly metformin is presently undergoing a thorough examination. Metformin is an oral biguanide, well established for the treatment of hyperglycaemia, that does not cause hypoglycaemia in normoglycaemic patients. It is an insulin sensitizer which reduces insulin secretion and, consequently, lowers circulating total and free androgen levels with a resulting improvement of the clinical sequelae of hyperandrogenism.
Importantly, it also seems to have a direct action on ovarian theca cells to decrease androgen production Attia et al. The indications for giving metformin to women with anovulatory PCOS have become progressively wider as it seems to be difficult to predict which individuals will respond well with this medication Fleming et al.
The difficulties of accurately measuring insulin sensitivity in all PCOS patients and the suggestion that metformin may also be effective in non-hyperinsulinaemic subjects Baillargeon et al. The wisdom of this strategy awaits ratification or, as noted by Harborne et al. Here I will consider the best available evidence for the treatment of anovulatory infertility with metformin, both as a single agent and in combination with CC. Metformin alone. The majority of these studies have demonstrated a significant improvement in insulin concentrations, insulin sensitivity and serum androgen concentrations, accompanied by decreased LH and increased sex hormone-binding globulin SHBG concentrations Nestler et al.
Fleming et al. Although significant, the increased frequency of ovulation was modest [relative risk RR 1. In a systematic review Kashyap et al. In a meta-analysis Lord et al. Interpretation of studies evaluating the effect of metformin as a sole agent for the induction of ovulation is made difficult by their heterogeneity as regards selection of patients whether hyperinsulinaemic, hyperandrogenaemic, diagnosis of PCOS, obese or slim, duration of metformin administration and dose, etc.
Although it now seems obvious that metformin is superior to placebo in inducing ovulation, none of the studies was powered to assess pregnancy as an outcome.
Comparisons of CC with metformin as single agents for the induction of ovulation and attainment of pregnancy must therefore await the results of a sufficiently powered randomized controlled trial RCT , directly comparing the two. The combination of CC and metformin, at the present state of knowledge, seems to be more effective than either CC or metformin given alone regarding both ovulation induction and pregnancy.
This would seem to be the case reflected by two meta-analyses Lord et al. As these results have not yet been officially published, judgment should be reserved, but initial enthusiasm will probably be dampened. It is, however, interesting to examine the individual published studies. Of those on metformin, 19 of 21 ovulated compared with two of 25 on placebo Nestler et al. The evidence is so far encouraging concerning the efficiency and safety of metformin as a single agent or in combination with CC for induction of ovulation in women with hyperinsulinaemic PCOS Homburg, In addition, metformin seem to be safe when continued throughout pregnancy, having no increase in congenital abnormalities, teratogenicity or adverse effect on infant development Glueck et al.
Preliminary data even suggest that this strategy can significantly decrease the high miscarriage rate usually associated with PCOS and reduce the incidence of gestational diabetes, pre-eclampsia and fetal macrosomia Glueck et al. The apparent lack of teratogenicity of metformin has earned it a B classification and, hopefully, these apparently beneficial effects of metformin given throughout pregnancy will be confirmed by future studies.
The glitazones, notably rosiglitazone and pioglitazone, which also have the property of lowering insulin concentrations, are also under investigation for similar indications.
A positive effect for rosiglitazone when used alone and more so when combined with CC was demonstrated for ovulation induction in women with PCOS Ghazeeri et al.
In women with PCOS but normal insulin sensitivity, metformin proved more efficient than rosiglitazone in restoring ovulation Baillargeon et al. Aromatase inhibitors are non-steroidal compounds that suppress estrogen biosynthesis by blocking the action of the enzyme aromatase which converts androstenedione and testosterone to estrogens.
Letrozole, the most widely used aromatase inhibitor, has mainly been employed for the treatment of post-menopausal women with advanced breast cancer. It is given orally in a dose of 2. It has been hypothesized, in particular by Mitwally and Casper , that the efficient estrogen-lowering properties of the aromatase inhibitors could be utilized to temporarily release the hypothalamus from the negative feedback effect of estrogen so inducing an increased discharge of FSH.
Although the final pathway, the sought-after discharge of FSH, is common to both aromatase inhibitors and CC, their mechanism of action is obviously very different and this would seem to confer several advantages to aromatase inhibitors for the induction of ovulation. Unlike CC, which blockades and depletes estrogen receptors, aromatase inhibitors have no effect on estrogen receptors. Aromatase inhibitors should, therefore, not have any deleterious effect on cervical mucus or endometrium, quite frequently a side effect of CC which interferes with the attainment of a pregnancy during ovulation induction therapy and is probably the main reason for the gap between ovulation and pregnancy rates.
This can theoretically be avoided when aromatase inhibitors are used for the same purpose. Only two of the included studies specifically compared letrozole and clomiphene as a single agent therapy. Although homogenous, the included studies were small in numbers. The results of the largest trial by Badawy et al, which was not included in the meta-analysis, do not match the conclusion of the meta-analysis [ 11 , 13 ].
Requena et al in their literature review looked at randomized trials comparing letrozole versus clomiphene as first line therapy and included four studies Atay et al ; Bayar et al ; Sorabvand et al ; Badawy et al [ 9 - 11 , 15 , 17 ]. The ovulation rate for letrozole in comparison with clomiphene did not differ significantly OR 1. A review of the clinical trial registry indicates that several trials reviewing the role of letrozole as an ovulatory inducing agent are underway and hopefully these will help in arriving at firmer conclusions [ 18 ].
The options for women not responding to increasing doses of clomiphene include insulin sensitizers, gonadotrophins, or laparoscopic ovarian drilling [ 19 , 20 ].
We conducted a randomized double blind placebo controlled trial using letrozole 2. The discrepancy in the ovulation rates could be attributed to either the dose of the drug chosen or to the small numbers studied. Letrozole was used as an adjunct for breast cancer treatment at a dose 2. A similar dose was followed for ovulation induction. Al Fahidi et al, looking at different dosage schedules 5 mgs vs. No multiple pregnancies were recorded in either group [ 23 ]. Summing up, Letrozole appears to an effective ovulation inducing agent in women with clomiphene resistance, though dosing issues still need to be resolved.
Quentero et al looked at the options available for women who failed to conceive despite ovulation following clomiphene therapy clomiphene failure [ 24 ]. There were 2 multiple pregnancies in the gonadotrophin group as compared to none in the letrozole group.
In comparison to gonadotrophins, letrozole is less expensive and requires less intense cycle monitoring, thus making it an option for women with clomiphene failure. Looking at the data from a different angle, additional pregnancies achieved in this group CC failure and in clomiphene resistant women, could be a possible explanation for the higher pregnancy rates obtained using letrozole as a first line in one of the earlier study [ 9 ].
Currently we do not have data to substantiate this argument. However first line use of letrozole will eventually generate information to answer such questions. An issue of great importance to couples seeking infertility treatment is the time to pregnancy.
Clinicians usually follow a step ladder approach in advising treatment: starting with the simplest and least expensive mode of therapy and then moving higher as required. However in certain clinical situations like advanced female age or severe endometriosis starting at a higher level would be more appropriate. However, conventionally one starts with a lower dose of clomiphene citrate, gradually building up the dose. Hence a diagnosis of either of these conditions is arrived at only after several months of therapy.
Letrozole has been shown to be effective in women with either clomiphene resistance or failure [ 4 , 24 ]. As pointed out by R. Casper using letrozole as first line therapy would logically help women bypass these problems thus avoiding superfluous treatment cycles, which would be especially useful in older women [ 25 ]. Intangible benefits are difficult to quantify or document but nevertheless are of importance to couples.
Letrozole has now been in use as an ovulation induction agent for more than a decade. Even though emerging evidence suggests that it is an effective ovulation induction agent, comparable if not better than clomiphene, it has still not gained universal acceptance for a variety of reasons. An abstract presentation at ASRM suggested an increase in congenital malformations following letrozole treatment.
The attention generated by this publication resulted in the manufacturers Novartis declaring that use of letrozole as an ovulation induction agent is contraindicated [ 26 ].
These observations were critically analyzed by Tulandi et al who presented additional data, assuaging fears regarding safety of letrozole [ 27 ].
However the worries and concerns continue and today letrozole has still not received approval for use in fertility treatment in the United States, Europe and many other parts of the world. Apart from denying anovulatory women access to a less expensive, simpler and effective treatment option, it has lead to a dearth of well designed trials assessing its role in infertility.
Once that minimum effective dosage is determined, physicians typically recommend the patient undergo four to six treatment cycles at that level until the patient successfully becomes pregnant.
The maximum dosage of clomiphene should not exceed — mg. These dosages have been found effective based on multiple clinical trials. Various methods that determine the exact timing of ovulation are blood tests for luteinizing hormone LH levels, urinary tests for LH levels, and ultrasounds to observe the condition of the pelvis.
During ovulation , the physician instructs patients to have intercourse every other day for one week beginning on the fifth day following the last dose. If the patient is unable to ovulate at the maximum daily dosage of — mg, the physician may combine clomiphene with other medications such as human chorionic gonadotropin hCG or dexamethasone. The addition of hCG to clomiphene therapy may benefit women who respond to clomiphene therapy with rising LH, follicle stimulating hormone FSH , and estrogen levels but still fail to ovulate.
Dexamethasone as an adjunct to clomiphene therapy benefits women with dehydroepiandrosterone sulfate DHEAS levels above the normal threshold. DHEAS is a precursor molecule to male and female sex hormones that can increase androgens male hormones in the body and result in infertility problems.
Clomiphene citrate causes ovulation by stimulating the pituitary gland to secrete more FSH and LH while stimulating the ovaries to secrete estrogen.
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