Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles
Clomiphene citrate and intrauterine insemination:analysis of more than 4100 cycles
Serena Dovey, Rita M. Sneeringer, M.D.,,and Alan S. Penzias,
a Boston IVF, Waltham, Massachusetts; b Division of Reproductive Endocrinology and Infertility, Department of Obstetrics andGynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and c Harvard Medical School, Boston,Massachusetts
Objective: To evaluate the outcomes of a large cohort of patients undergoing fertility treatment with clomiphenecitrate and intrauterine insemination. Design: A retrospective cohort study. Setting: Boston IVF, a large university-affiliated reproductive medicine practice. Patient(s): A total of 4,199 cycles performed in 1,738 infertility patients between September 2002 and July 2007. Intervention(s): All patients received oral clomiphene citrate, and patients with completed cycles had intrauterineinsemination performed. Main Outcome Measure(s): Cumulative and per cycle pregnancy rates achieved among subsets of patients definedby age, completed cycles, and intention to treat (ITT). Result(s): For women under age 35 years, 2,351 cycles were initiated in 983 patients. A total of 238 pregnanciesensued, yielding a pregnancy rate (PR) per completed cycle of 11.5% and 10.1% per cycle initiated with ITT. Inwomen aged 35–37 years, 947 cycles in 422 women lead to a PR per completed cycle and ITT of 9.2% and 8.2%,respectively. For patients aged 38-40 years, 614 cycles in 265 women lead to a PR per completed cycle and ITT of7.3% and 6.5%, respectively. In women aged 41–42 years, 166 cycles in 81 patients lead to a PR per completedcycle and ITT of 4.3% and 3.6%, respectively. For women above age 42 years, 120 cycles in 55 patients lead toa PR per completed cycle and ITT of 1.0% and 0.8%, respectively. On a per-patient treated basis, cumulativePRs were 24.2% under age 35, 18.5% ages 35–37, and 15.1% ages 38–40, whereas only 7.4% ages 41–42 and1.8% above 42 became pregnant (one pregnancy in 55 patients). Conclusion(s): As anticipated, younger patients have a higher PR per cycle than older patients. The PR per cyclefor patients who initiate only one or only two treatment cycles is notably higher than the corresponding per cyclerates for cycles 3 through 9. The drop in success per patient among 41- and 42-year-olds is sharp, but the excep-tionally low success rate above age 42 suggests that CC with IUI has virtually no place in their treatment. (FertilSterilÒ 2008;90:2281–6. Ó2008 by American Society for Reproductive Medicine.)
Key Words: Clomiphene citrate, intrauterine insemination, infertility, assisted reproductive technology, artificialinsemination, ART outcomes
Clomiphene citrate (CC) has been a treatment of choice to
receptors. By effectively diminishing the pool of available
help correct ovulatory dysfunction and treat infertility for
estrogen receptors within the hypothalamus, the negative
over 40 years. Clomiphene citrate is both an agonist and
feedback signal induced by estrogen is blocked, which in
antagonist of estrogen, generally acting as a competitive
turn, alters pulsatile GnRH secretion. This altered GnRH
estrogen antagonist at physiologic female estrogen levels
secretion then enhances gonadotropin release from the pitui-
Clomiphene citrate is able to stimulate ovulation by com-
tary. Increased gonadotropin release ultimately drives
peting with estrogen for binding to the hypothalamic estrogen
folliculogenesis at the level of the ovary
Given its ability to induce ovulation in oligo-ovulatory and
Received August 30, 2007; revised and accepted October 31, 2007.
anovulatory females, CC is considered a first-line medical
Presented at the Society for Gynecologic Investigation, 54th Annual
approach to improve fertility in this patient population
Scientific Meeting Reno, Nevada, March 14–17, 2007.
Hammond et al. demonstrated that, in a group of an-
Conflicts of interest: Serena Dovey, no conflicts to report; Rita Sneeringer,
no conflicts to report; Alan Penzias, Ferring Pharmaceuticals—Re-
ovulatory and oligomenorrheic women treated with CC,
search Grant Support; Speakers Bureau; EMD Serono and Organon,
86% ovulated and 49% of those patients conceived. More
recently, in a compilation of seven published studies looking
Reprint requests: Alan S. Penzias, M.D., Boston IVF, 130 Second Avenue,
at CC and ovulation, Homburg reported an ovulation rate
of 73% with a pregnancy rate (PR) of 36%. In addition, Beck
Fertility and Sterilityâ Vol. 90, No. 6, December 2008
Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
et al. analyzed 12 randomized controlled trials regarding
is achieved through a hysterosalpingogram. A semen analysis
oral antiestrogen treatment in patients with anovulatory infer-
is also performed. In 2007, a basal antral follicle ultrasound
tility and concluded that CC is effective in increasing the PR
was added to the evaluation. Upon completion of the initial
when compared with placebo. Thus, CC effectively stimu-
evaluation patients with evidence of thyroid dysfunction or
lates both ovulation and greatly improves fertility success
hyperprolactinemia were further evaluated as indicated, and
treated medically before proceeding with fertility therapy. Men with severe semen parameter abnormalities were
Given the fertility success seen in the anovulatory popula-
referred for urologic evaluation. Patients were deemed eligi-
tion, CC has more recently been used as an approach to initial
ble for ovulation induction and IUI if they had at a structurally
treatment in patients with unexplained infertility, on the
normal uterine cavity with at least one open fallopian tube
premise that CC will increase the number of mature follicles
without radiographic evidence of peritubal adhesions, were
that develop every month and thus increase the likelihood of
ovulatory or oligo-anovulatory, and had adequate sperm
pregnancy. Additionally, it has been postulated that CC may
available for insemination defined as the presence at least 5
help to overcome subtle ovulatory defects . In a retro-
million total motile sperm postprocessing. Thus, the patients
spective analysis of 45 published studies on CC success in pa-
treated in the present analysis represent multiple infertility
tients with unexplained infertility, Guzick reported a 5.6%
diagnoses. Treatment with CC began at a dose of 50 mg in
PR per cycle in patients undergoing CC treatment with timed
oligo-anovulatory patients or 100 mg in ovulatory infertile
intercourse, and an 8.3% PR per cycle in CC plus intrauterine
patients for 5 consecutive days. Cycles were cancelled
insemination treatment (CC/IUI). Furthermore, in one of the
when the patient [1] failed to respond to the prescribed
largest series to date, Dickey et al. reported a 9.2% PR per
dose of CC as evidenced by the absence of an LH surge using
cycle in 3,381 CC/IUI cycles in a population of infertility
a home-based urine ovulation predictor kit and confirmed by
patients that included both ovulatory and anovulatory
the absence of at least one follicle >15 mm by pelvic ultra-
patients. Thus, given that CC is an orally administered,
sound, [2] ovulated spontaneously before scheduled cycle
cost-effective means of improving PRs among a variety of
monitoring as evidenced by a serum progesterone >3 ng/
patients, it can be reasonably argued that it should be the first
mL, or [3] had no motile sperm detected following sperm-
therapy offered to patients seeking infertility treatment.
washing procedures. Patients whose treatment cycles were
However, the reported efficacy of CC varies widely in the
published literature. In the ovulatory infertility population,published PRs per cycle with CC range anywhere from12% to 35% . In an infertility population consisting
of both ovulatory and anovulatory patients, efficacy rates of
In September 2002, Boston IVF began using an electronic
CC are even more variable, with published PRs ranging
medical record (eIVF, PracticeHwy.com, Inc, Irving, TX)
from 4% to 27% per cycle . In this study, we report
to track cycles of ovulation induction and IUI. All patients
the largest series of CC data to date in a population of infertile
undergoing ovarian stimulation with or without IUI at Boston
patients who were either ovulatory or oligo-anovulatory, with
IVF between September 2002 and the present are in the data-
at least one open fallopian tube undergoing IUI. We also
base. The database contains in excess of 10,000 ovarian stim-
stratify the efficacy of CC by age groups and examine out-
ulation cycles. Using the eIVF database query tool, data from
come on a per-cycle and per-patient-treated basis to highlight
all cycles of CC with IUI were exported in July 2007 to
when CC is effective and when it should be bypassed in favor
a Microsoft Excel spreadsheet for analysis.
of other treatment alternatives that may better maximizepregnancy success.
Information recorded in the database for each stimulation
cycle included a unique numeric patient identifier, thepatient’s name, age at cycle start, treatment start date, last
menstrual period, peak estradiol level, pregnancy outcome,
and cancellation date and cancellation reason (if applicable). The cycle outcome descriptions logged within the database
All patients in the present study were evaluated and treated at
included the following: pregnant, not pregnant, cancelled,
Boston IVF, a large university affiliated reproductive medi-
stopped, in progress, blank, or awaiting results. Pregnancy
cine practice. The data analysis was performed under an
as defined in our study include only those patients who had
institutional review board protocol approved by Beth Israel
ultrasound evidence of a gestational sac. A separate field in
Deaconess Medical Center. Patients in the data set ranged
the database ‘‘pregnancy test’’ with possible entries of posi-
in age from 20–48 years, with a mean age of 34.5 years.
tive or negative was not included in this analysis. We found
All patients underwent a comprehensive fertility evaluation.
that a large percentage of subjects had a blank entry in the
At Boston IVF a comprehensive fertility evaluation includes
‘‘pregnancy test’’ field, indicating that the field was not
cycle day 3 measurement of estradiol, FSH, TSH, free thy-
consistently recorded at the time of cycle closure.
roxin, and prolactin. Women aged 40 and older also undergoa CC challenge test to further assess their ovarian reserve.
The eIVF Query tool identified 4,229 cycles of CC with
Assessment of uterine anatomy and fallopian tube patency
IUI. Thirty cycles were removed from the analysis as they
Clomiphene/intrauterine insemination results in 4100 cycles
belonged to hypothetic test patients placed into the electronic
For women above age 42 years, 120 cycles in 55 patients
medical record for training purposes.
yielded one pregnancy, a rate of 1.8% per patient. The PRper completed cycle and ITT were 1.0% and 0.8%, respec-
Each record in the database represented an individual
cycle. Because each patient undergoing treatment hasa unique identifier it was possible to identify each patient.
With the exception of ages 41–42, approximately 90% or
There were a total of 1,738 patients who initiated 4,199 treat-
more of the pregnancies seen in each age stratum was
ment cycles. It was further possible to determine the number
achieved in three initiated CC/IUI cycles or fewer (
of cycles each patient undertook. The data shows that 95% ofthe patients initiated four cycles of CC/IUI or fewer. In thisanalysis we chose to examine individual cohorts of patients
as a function of the number of treatment cycles initiated.
This study is the largest single-center study to date reporting
Therefore, patients who initiated three cycles are not a nested
on the efficacy of CC and IUI. Although the variation among
subset of those who initiated four cycles.
CC success rates in the literature is wide, our PR per cycle doescorrelate closely with some of the larger published trials
The data was stratified by patient age at cycle start into five
categories. Four of the categories are concordant with the age
Our study is unique in that we have analyzed both the PR
strata used by the United Stated Department of Health and
per cycle but further stratified by the number of initiated
Human Services, Centers for Disease Control and Prevention
cycles. Patients continue or discontinue treatment with CC/
in their annual Assisted Reproductive Technology Report.
IUI for a number of reasons. Treatment-dependent pregnancy
They are: [1] <35 years of age, [2] 35 to 37, [3] 38 to 40,
is clearly one reason for discontinuation, but other reasons for
and [4] 41 to 42. The final stratum in the present study was
discontinuation include treatment-independent pregnancy,
moving on to alternative treatment options or child-freeliving, financial constraints, and stress
The data is further stratified by the number of cycles initi-
ated by each patient, ranging from 1 to 9. Outcomes are
We chose to report PRs where the results were clearly
reported in three ways for each age stratum by number of
known as well as by ITT. By doing so we hoped not to bias
cycles initiated: [1] pregnancy rate per cycle of known out-
the results by showing only completed cycles. If there was
come (pregnant or not pregnant), [2] pregnancy rate per cycle
a significant dropout or cancellation rate at a particular age
initiated regardless of outcome status (intention to treat), and
or cycle number we believed that studying the two extreme
ends of outcome calculation that we would be able to detectsuch an anomaly, if it existed. The largest difference between% pregnant with known outcome and % pregnant by ITT was
seen in all age strata (except those >42) among patients who
The statistical package available in Excel was used to calcu-
initiated only one cycle. This is not a surprise in that patients,
who for one reason or another, had a cycle cancelled, wouldbe less likely to proceed on to another cycle. The lack of dif-ference in the oldest age stratum is because of the lack of
pregnancy among any of the 25 patients who initiated theirfirst cycle of CC/IUI at that age.
For women under age 35 years, 2,351 cycles were initiated in983 patients. A total of 238 pregnancies ensued yielding
Our data demonstrated a PR per cycle that is higher than the
a pregnancy rate (PR) per completed cycle of 11.5% and
PR among natural cycles in patients with unexplained infertil-
10.1% per cycle initiated with intention to treat (ITT).
ity. In a retrospective analysis of 45 published reports looking
Among the 938 patients in this age category treated, 24.2%
at the efficacy of various ovulation induction protocols, Guzick
et al described a natural PR per cycle of only 1.3%–4.1% inan unexplained infertility population. Thus, we can infer that
In women aged 35–37 years, 947 cycles in 422 women lead
CC/IUI increases the chance of pregnancy two- to 10-fold
to a PR per completed cycle and ITT of 9.2% and 8.2%,
over timed intercourse in this patient population.
respectively. The 422 patients in this age category achieved78 pregnancies for a rate of 18.5%.
In addition, patients who initiate any treatment are inter-
ested in knowing if their chance of conception declines
For patients aged 38–40 years, 614 cycles in 265 women
over repeated months of treatment. We looked at the % of
lead to a PR per completed cycle and ITT of 7.3% and
all pregnancies achieved in each age stratum as a function
6.5%, respectively. There were 40 pregnancies in the 265
of the number of cycles initiated. For women aged 40 and
younger 89%–95% are achieved with three or fewer cycles
In women aged 41–42 years, 166 cycles in 81 patients
initiated with 92%–98% achieved with four or fewer cycles
lead to a PR per completed cycle and ITT of 4.3% and
initiated. The same was not observed for patients aged 41–
3.6%, respectively. Only 6 of the 81 patients (7.4%) became
42; however, there were only six pregnancies achieved in
the 166 cycles initiated in 81 patients. Thus, the overall low
Cycle Cycles Cycles Cycles Cycles Cycles Cycles Cycles Cycles
16.5% 13.5% 19.2% 50.0% 33.3% 50.0% 100.0%
1 Cycle 2 Cycles 3 Cycles 4 Cycles 5 Cycles 6 Cycles 7 Cycles
Dovey. Clomiphene/intrauterine insemination results in 4100 cycles. Fertil Steril 2008.
Clomiphene/intrauterine insemination results in 4100 cycles
a Total cycles initiated ¼ intention to treat þ patient not pregnant þ patient pregnant.
Dovey. Clomiphene/intrauterine insemination results in 4100 cycles. Fertil Steril 2008.
PR in that age group makes the percentage less relevant.
coids, and gonadotropins, with promising preliminary
Because the overwhelming majority of pregnancies to be
achieved with each age stratum occur within three to four ini-
Another concern broached in recent publications is whether
tiated cycles, there seems to be little benefit to continued use
the antiestrogen effects of CC interfere with implantation and
pregnancy Several invesitgators have noted that PRs
Our data also highlights a significant reduction in efficacy of
with CC are less than expected based on achieved ovulation
CC/IUI with advancing maternal age. This finding is not sur-
rates, and this discrepancy has been theorized to be secondary
prising, given that an overall decline in fertility with advancing
to CC’s antiestrogenic effects on cervical mucus and endome-
age has been well documented In our population,
trial differentiation. It has been suggested that the aromatase
women 41 and 42 years old only had a 3.6%–4.3% PR per cy-
inhibitor class of medications, which are not associated with
cle with CC/IUI, and only 7.4% of the patients ever achieved
such adverse antiestrogen effects, may thus replace CC as
pregnancy with this modality. This rate is less than half the
the mainstay of infertility therapy However, trials
pregnancy incidence per patient of women aged 38–40.
comparing the efficacy of CC to letrozole, one of the most
Patients who were 43 years of age and older only had a 1%
or less PR per cycle. More pointedly, only 1 patient of 55
treated ever achieved a pregnancy. This suggests the absenceof efficacy of CC/IUI for patients age 43 years and older.
Although CC/IUI has been the mainstay of initial therapy
for both oligo-anovulatory infertility as well as unexplained
infertility for many years, concerns have been raised in the
literature regarding its overall efficacy in certain patient pop-ulations . Specifically, some studies have identified
a subset of anovulatory women who are resistant to CC
. The incidence of CC resistance is approximately 25%,
and although the etiology behind failure to ovulate is unclear,
studies have demonstrated that these patients tend to be obese
and insulin resistant However, several therapiesare being studied in this patient population to use in conjunc-
Dovey. Clomiphene/intrauterine insemination results in 4100 cycles. FertilSteril 2008.
tion with CC, such as insulin-sensitizing agents, glucocorti-
commonly used aromatase inhibitors, have yet to demonstrate
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PROSTATE CARCINOMA ASCO 2006 2508. MDX-010 Ipilimumab (antiCTLA-4)0.5-3 mg/kg d 1 + GMCSF 250 mg/m2/d x 14 d. Prostate cancer: PSA reduction <50% 7/18. Dose response effect with increase in CD4+ and CD8+ T cells. **4560. Prostate ca. Premarin 1.25 mg tid (high dose). 32% PSA response rate after antiandrogen failure. Low dose 1.25 mg qd no effect. 4565. Prostate ca. Addition of somatostatin to
To effectively treat and manage Alzheimer’s disease and related disorders (ADRD), it is necessary to focus on improved care, nutrition, environment and physical health. Problems may also arise from lack of mobility, lack of stimulation (boredom), and social isolation. There are currently five medications approved by the FDA for the treatment of Alzheimer’s disease (AD): Aricept, Exelo