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555. Carrell DT, Cartmill D, Jones KP, Hatasaka HH, Peterson CM, Prospective, randomized, blinded
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556. Kolettis PN, Thomas AJ Jr, Vasoepididymostomy for vasectomy reversal: a critical assessment in the era of
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557. Pavlovich CP, Schlegel PN, Fertility options after vasectomy: a cost-effectiveness analysis, Fertil Steril
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558. Schlegel PN, Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A cost-
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559. Donovan JF Jr, DiBaise M, Sparks AE, Kessler J, Sandlow JI, Comparison of microscopic epididymal
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560. Kolettis PN, D’Amico AM, Box L, Burns JR, Outcomes for vasovasostomy with bilateral intravasal
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561. Matthews GJ, Schlegel PN, Goldstein M, Patency following microsurgical vasoepididymostomy and
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562. Goldstein M, Li PS, Matthews GJ, Microsurgical vasovasostomy: the microdot technique of precision suture
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563. Kolettis PN, Woo L, Sandlow JI, Outcomes of vasectomy reversal performed for men with the same female
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564. Kolettis PN, Sabanegh ES, D’Amico AM, Box L, Sebesta M, Burns JR, Outcomes for vasectomy
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565. Fuchs EF, Burt RA, Vasectomy reversal performed 15 years or more after vasectomy: correlation of
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566. Paick JS, Park JY, Park DW, Park K, Son H, Kim SW, Microsurgical vasovasostomy after failed
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572. Turek PJ, Seminal vesicle and ejaculatory duct surgery, In: Graham SD Jr, ed. Glenn’s Urologic Surgery,
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573. Cornel EB, Dohle GR, Meuleman EJ, Transurethral deroofing of midline prostatic cyst for subfertile men,
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574. Schroeder-Printzen I, Ludwig M, Kohn F, Weidner W, Surgical therapy in infertile men with ejaculatory
duct obstruction: technique and outcome of a standardized surgical approach, Hum Reprod 15:1364, 2000.

575. Purohit RS, Wu DS, Shinohara K, Turek PJ, A prospective comparison of 3 diagnostic methods to evaluate
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576. Kadioglu A, Cayan S, Tefekli A, Orhan I, Engin G, Turek PJ, Does response to treatment of ejaculatory
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577. Paduch DA, Niedzielski J, Repair versus observation in adolescent varicocele: a prospective study, J Urol
158:1128, 1997.

578. Sigman M, Jarow JP, Ipsilateral testicular hypotrophy is associated with decreased sperm counts in infertile
men with varicoceles, J Urol 158:605, 1997.

579. Chehval MJ, Purcell MH, Deterioration of semen parameters over time in men with untreated varicocele:
evidence of progressive testicular damage, Fertil Steril 57:174, 1992.

580. Witt MA, Lipshultz LI, Varicocele: a progressive or static lesion? Urology 42:541, 1993.
581. Matthews GJ, Matthews ED, Goldstein M, Induction of spermatogenesis and achievement of pregnancy

after microsurgical varicocelectomy in men with azoospermia and severe oligoasthenospermia, Fertil Steril
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582. Kim ED, Leibman BB, Grinblat DM, Lipshultz LI, Varicocele repair improves semen parameters in
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583. Goldstein M, Gilbert BR, Dicker AP, Dwosh J, Gnecco C, Microsurgical inguinal varicocelectomy with
delivery of the testis: an artery and lymphatic sparing technique, J Urol 148:1808, 1992.
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589. Madgar I, Weissenberg R, Lunenfeld B, Karasik A, Goldwasser B, Controlled trial of high spermatic
vein ligation for varicocele in infertile men, Fertil Steril 63:120, 1995.
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counselling as effective as occlusion of the vena spermatica, Hum Reprod 13:2147, 1998.
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change the way couples use assisted reproductive technologies? J Urol 167:1749, 2002.
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in spinal cord injured men: sperm quality and patient preference, J Urol 157:2147, 1997.
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single spermatozoon into an oocyte, Lancet 340:17, 1992.
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sperm aspiration for sperm retrieval: a study of urological outcomes, Hum Reprod 13:1260, 1998.
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27

Induction of Ovulation

Although it seems commonplace today, indeed even routine, the ability to induce
ovulation and attain pregnancy in anovulatory infertile women remains one of the
greatest achievements of reproductive endocrinology. Once limited to clomiphene
citrate, the therapeutic armamentarium for ovulation induction now includes a wide
variety of agents.

Ovulatory disorders can be identified in 18–25% of infertile women.1 When
anovulation is the only infertility factor, the prognosis for pregnancy generally is quite
good because modern ovulation induction strategies are highly effective. When a
specific cause for anovulation can be identified, treatment often restores normal cycle
fecundity. Even when no specific cause can be found, as in most anovulatory women,
empiric treatments with low costs and risks usually succeed. When those fail, other
more complex forms of treatment are effective. One way or another, almost all
anovulatory infertile women can be induced to ovulate. Unfortunately, many still do not
conceive, often because there are other coexisting infertility factors.

Clinicians caring for infertile couples must have a thorough understanding of the
methods for treatment of anovulatory infertility. This chapter reviews the principles that
guide the choice of treatment, the results achieved with different therapies, and their
associated risks.

DIAGNOSIS OF ANOVULATION

The diagnosis of anovulation generally is not difficult to establish. Women with
irregular, unpredictable, or infrequent menses do not require specific diagnostic
tests to prove what is already obvious. When anovulation is suspected but uncertain, a
variety of methods can be used to evaluate ovulatory function, as discussed in Chapter
25 and summarized briefly here.

Ovulatory cycles typically are associated with a classic “biphasic” basal body
temperature (BBT) pattern that is not difficult to recognize, when present.2 BBT
recordings having no sustained interval of temperature elevation preceding the
onset of menses strongly suggest anovulation. Biphasic recordings exhibiting a short
luteal phase (onset of menses <12 days after the midcycle rise in BBT) suggest a subtle,
but still important, form of ovulatory dysfunction. Although uncommon, BBT recordings
are not clearly biphasic in some ovulatory women. Since BBT cannot reliably define the
time of ovulation and can become tedious, it is not the method of choice for evaluating
ovulatory function for most infertile women.3

A serum progesterone measurement is the simplest, most common, objective,
and reliable test of ovulatory function, as long as it is appropriately timed. A
progesterone concentration less than 3 ng/mL implies anovulation, except when
drawn immediately after ovulation or just before the onset of menses, when lower
levels naturally might be expected.4,5 A normal ovulatory cycle is 25–35 days in
duration and exhibits a luteal phase lasting approximately 14 days. Ideally, the serum
progesterone level should be drawn approximately 1 week before the expected
onset of menses, when the concentration is at or near its peak. Contrary to popular
belief and practice, cycle day 21 is not always the best time to measure the serum
progesterone concentration and the threshold level indicating ovulation is not 10
ng/mL. Cycle day 21 is a good choice for women with cycles lasting approximately 28
days but a poor choice for women with 35-day cycles. A serum progesterone
concentration greater than 10 ng/mL suggests normal luteal function but not when the
luteal phase is grossly short, and a level less than 10 ng/mL can be quite normal,
because progesterone is secreted by the corpus luteum in distinct pulses, temporally
linked to pulsatile luteinizing hormone (LH) secretion6; random sampling can coincide
with a transient nadir in serum levels. If the menses does not commence 7 days after
a serum progesterone reading of less than 3 ng/mL, it may be reasonable to repeat
the test.

Other simple tests of ovulation include monitoring urinary LH excretion. This has
been simplified by the wide availability of home urine LH kits that are designed to

detect a high LH value at the time of the LH surge. More sophisticated test available for
home use also includes a measure of rising estrogen production preceding the LH surge.
Serial transvaginal ultrasonography can be useful once ovulation has been achieved but
is unnecessary and not always accurate for the diagnosis of anovulation. Ruptured
follicles can refill with fluid, and a nondominant follicle that has progressed in size can
be mistaken for the missing follicle.

CLASSIFICATION OF OVULATORY
DISORDERS

After evaluation for the causes of anovulation is completed, virtually all women can be
classified according to the criteria adopted by the World Health Organization (WHO).7
Hyperprolactinemic anovulation is considered as a fourth and specific category.

WHO Group I: Hypogonadotropic Hypogonadal

Anovulation

The group accounts for approximately 5–10% of anovulatory women and includes those
with low or low-normal serum follicle-stimulating hormone (FSH) concentrations and
low serum estradiol levels, due to absent or abnormal hypothalamic gonadotropin-
releasing hormone (GnRH) secretion or pituitary insensitivity to GnRH. Examples
include women with hypothalamic amenorrhea relating to physical, nutritional, or
emotional stress; weight loss; excessive exercise; anorexia nervosa and its variants;
Kallmann syndrome; and isolated gonadotropin deficiency. Women in the group may
require hypothalamic-pituitary imaging to exclude a mass lesion.

WHO Group II: Normogonadotropic

Normoestrogenic Anovulation

This group is the largest, including 75–85% of anovulatory women, and is characterized
by normal serum FSH and estradiol levels and normal or elevated LH concentrations.8
The most common examples are women with polycystic ovary syndrome (PCOS), some
of whom ovulate at least occasionally. Women with PCOS should be assessed for
cardiovascular disease risk factors and glycemic status.9

WHO Group III: Hypergonadotropic

Anovulation

The group accounts for approximately 10–20% of anovulatory women and includes
those with elevated serum FSH and low AMH concentrations; most, but not all, have
amenorrhea. The classic example is premature ovarian insufficiency, due to follicular
depletion, and few respond to treatment aimed at ovulation induction.

Hyperprolactinemic Anovulation

Approximately 5–10% of anovulatory women have hyperprolactinemia, which inhibits
gonadotropin secretion. Consequently, serum FSH concentrations generally are low or
low-normal, and serum estradiol levels also tend to be relatively low. Most
hyperprolactinemic women have oligomenorrhea or amenorrhea. When
hyperprolactinemia cannot be attributed confidently to coexisting hypothyroidism or to
medications, hypothalamic-pituitary imaging is indicated to exclude a mass lesion.

PRETREATMENT EVALUATION AND
TREATMENT

The causes of anovulation are many and varied. Thyroid disease, hyperprolactinemia,
adrenal disease, pituitary or ovarian tumors, eating disorders, extremes of weight loss
or exercise, PCOS, and obesity all are commonly associated with ovulatory
dysfunction. Treatment should be directed at the underlying cause, when that can be
determined, because specific treatment is more likely to succeed and some conditions
can have longer-term health consequences if not recognized and treated.

All anovulatory women deserve at least some preliminary evaluation, both to
exclude important pathology that may require medical attention before ovulation
induction begins and to identify the most likely successful form of treatment.
Chapter 10 considers the causes and management of amenorrhea and galactorrhea.
Chapters 11 and 12 discuss the pathophysiology and treatment of PCOS and hirsutism.
Chapter 15 describes the evaluation of abnormal uterine bleeding. At a minimum,
anovulatory women should be screened for thyroid disorders (serum TSH) and
hyperprolactinemia (serum prolactin) because both require further evaluation and
specific treatment.10,11,12 Depending on the menstrual history, endometrial sampling also
merits consideration, because chronic anovulation is associated with increased risk for
endometrial hyperplasia. Persistently thick endometrium, prolonged amenorrhea,
abnormal vaginal bleeding, or excess weight should require investigation for
endometrial cancer in women with PCOS.9

Glycemic status should be assessed at baseline in all women with PCOS. In
high-risk patients, that is, with a BMI greater than 25 kg/m2, history of impaired
fasting glucose, impaired glucose tolerance or gestational diabetes, family history
of diabetes mellitus type 2, hypertension, or high-risk ethnicity, oral glucose
tolerance test is recommended.9 Even though OGTT is the preferred method of
testing for impaired glucose tolerance and early type 2 diabetes, fasting plasma
glucose or HbA1C levels can suffice for others.9 When OGTT is done, 2 hours after a
75 g oral glucose load, glucose concentrations between 140 and 199 mg/dL indicate
impaired glucose tolerance and levels of 200 mg/dL or greater indicate non–insulin-
dependent diabetes.

Anovulation offers an obvious potential explanation for infertility but often is not
the only infertility factor. Before ovulation induction begins, a screening semen
analysis is prudent because male factors are an important contributing cause in 20–
40% of infertile couples.13 Early recognition of a significant coexisting male factor
helps to avoid wasted time, effort, expense, and associated frustrations.

Additional preliminary evaluation with hysterosalpingography (HSG) or
transvaginal ultrasonography merits serious consideration, particularly in women with a
history of previous pelvic infection or surgery, ectopic pregnancy, inflammatory bowel
disease, pelvic pain or other symptoms of endometriosis, or an abnormal physical
examination. In the absence of such risk factors, the likelihood of tubal disease is low
and HSG can be deferred safely in young women and those who do not require
complicated and costly forms of ovulation induction. In older women with a narrowing
window of opportunity, it is generally wise to evaluate objectively all relevant
infertility factors before treatment begins to ensure that time is used to the best possible
advantage. In women who require ovulation induction with exogenous gonadotropins,
the associated costs, logistics, and risks also justify a thorough preliminary evaluation.

Preliminary HSG and transvaginal ultrasonography are recommended when the

medical history or physical examination raises suspicion for coexisting uterine or

tubal infertility factors, for women over age 35, and when ovulation induction
requires treatment with exogenous gonadotropins. Laparoscopy and hysteroscopy
are unnecessary for most women but certainly appropriate for those with an abnormal
HSG or signs or symptoms of pelvic disease.

Lifestyle management for weight loss is recommended for PCOS patients with a
BMI greater than 25 kg/m2. Even modest weight loss (5–10% of body weight) often
restores ovulatory cycles in obese anovulatory women with PCOS.14,15,16,17,18,19,20 In
overweight and obese women with PCOS, unless age-related infertility is a concern,
intensive lifestyle modification, including hypocaloric diet and exercise, with or
without behavioral interventions, may be the first-line treatment for 3–6 months, to
determine whether ovulation is resumed.9 At a minimum, weight loss can increase
sensitivity to ovulation-inducing drugs and decrease the complexity of treatment
required. In one study, 60 of 67 obese anovulatory women (90%) who lost an average
of 10 kg/m2 in a diet and exercise program resumed spontaneous ovulation and 52
(78%) ultimately achieved pregnancy, 18 (27%) without other interventions.20 In
another study, 149 infertile women with PCOS were randomly allocated to (1)
continuous oral contraceptive pills (OCP); (2) lifestyle modification consisting of
caloric restriction with meal replacements, weight loss medication (either sibutramine
or orlistat), and increased physical activity to promote a 7% weight loss; or (3)
combined treatment with both OCP and lifestyle modification, for 16 weeks prior to
four cycles of ovulation induction with clomiphene and timed intercourse.21 Women
receiving lifestyle modification or combined lifestyle modification with OCP achieved
significant weight reduction (−6.2% and −6.4%, respectively) and had significantly
higher cumulative ovulation rates than women receiving OCP (60%, 67%, and 46%,
respectively).21 Compared to similar women who received clomiphene right away in

another randomized trial,22 women receiving lifestyle modification in the
aforementioned trial achieved significantly higher cumulative ovulation (lifestyle, RR =
1.4; 95% CI = 1.1–1.7; combined, RR = 1.4; 95% CI = 1.2–1.8) and significantly better
live birth rates (lifestyle, RR = 2.5; 95% CI = 1.3–4.7 and combined, RR = 2.5; 95% CI
= 1.3–4.8).22,23

Bariatric surgery can be considered as a second-line treatment option when
significant obesity (BMI > 35 kg/m2) and anovulation are resistant to lifestyle
intervention and/or pharmacotherapy, especially in the presence of obesity-related
comorbidities.9,24 Even though bariatric surgery improves anovulation, hirsutism,
insulin resistance, sexual activity, and libido, whether maternal and fetal outcomes are
improved is uncertain.25,26 A 2016 meta-analysis, including 13 case series with 2,130
PCOS patients who underwent bariatric surgery, reported that 12 months after surgery,
the incidence of PCOS decreased to 6.8% from 45.6%, menstrual irregularity to 7.7%
from 56.2%, and hirsutism to 38.6% from 67.0%.25 The incidence of preoperative
infertility was 18.2%, which significantly decreased to 4.3% at study end.25 A 2017
meta-analysis corroborated these findings and furthermore reported 96% (CI = 88–
100%) resolution rate for PCOS among 82 severely obese patients.27 Bariatric surgery
can cause malabsorption and eating disorders, which may adversely affect maternal and
neonatal health. Risks of small-for-gestational-age babies, preterm delivery, and,
possibly, neonatal mortality seem to increase after bariatric surgery. Therefore, it is
recommended to avoid pregnancy during rapid weight loss and for at least 12 months
after bariatric surgery. In sum, bariatric surgery is considered an experimental therapy
for infertility associated with PCOS.9

CLOMIPHENE CITRATE

Clomiphene citrate was first synthesized in 1956, introduced for clinical trials in 1960,
and approved for clinical use in the United States in 1967.28,29 In early clinical trials,
60–80% of anovulatory women treated with clomiphene achieved ovulation and half of
those who ovulated also conceived.28,29,30 The collected clinical experience gained in
the years since remains consistent with those early observations.

Pharmacology and Mechanism of Action

Clomiphene is a nonsteroidal triphenylethylene derivative that acts as a selective
estrogen receptor modulator (SERM), having both estrogen agonist and antagonist
properties.31 However, in almost all clinical circumstances, clomiphene acts purely as
an antagonist or antiestrogen; its weak estrogenic actions are clinically apparent only
when endogenous estrogen levels are very low. Clomiphene is cleared through the liver
and excreted in the stool; approximately 85% is eliminated within a week, but traces
can remain in the circulation for a longer time.32 Clomiphene is a racemic mixture of
two different stereoisomers, enclomiphene (62%, originally known as cis-clomiphene)
and zuclomiphene (38%, originally known as trans-clomiphene).31,33 Enclomiphene is
the more potent isomer and the one responsible for its ovulation-inducing actions.31,34
The half-life of enclomiphene is relatively short, so serum concentrations rise and fall
quickly during and after treatment.32,35 Zuclomiphene is cleared much more slowly;
serum levels remain detectable for weeks after a single dose32 and may even accumulate
gradually over a series of cycles, but there is no evidence that residual zuclomiphene
has any important clinical effects or consequences.35

Structural similarity to estrogen allows clomiphene to compete with endogenous
estrogen for nuclear estrogen receptors at sites throughout the reproductive system.
However, unlike estrogen, clomiphene binds to nuclear estrogen receptors for an
extended interval of time and thereby depletes receptor concentrations by interfering
with receptor recycling.31 At the hypothalamic level, estrogen receptor depletion
prevents accurate interpretation of circulating estrogen levels; circulating estrogen
levels are perceived as lower than they truly are. Reduced negative estrogen
feedback triggers normal compensatory mechanisms that alter the pattern of
GnRH secretion and stimulate increased pituitary gonadotropin release, which, in
turn, drives ovarian follicular development. In the pituitary, clomiphene also may
increase the sensitivity of gonadotrophs to GnRH stimulation (Figure 27.1).36

FIGURE 27.1

When administered to already ovulatory women, clomiphene increases GnRH pulse
frequency.37 In anovulatory women with PCOS who already exhibit an increased GnRH
pulse frequency, clomiphene increases only pulse amplitude.38 Serum levels of both
FSH and LH rise during clomiphene treatment and fall again soon after the typical 5-day
course of therapy is completed.39 In successful treatment cycles, one or more follicles
emerge and grow to maturity. In parallel, serum estrogen levels rise progressively,
ultimately triggering an LH surge and ovulation. In sum, clomiphene works primarily by
stimulating the normal endocrine mechanisms that define the hypothalamic-pituitary-
ovarian feedback axis. The importance of other effects it may have on insulin-like
growth factors (decrease in IGF-I concentrations) and sex hormone–binding globulin
(increase in serum levels) is uncertain.40,41

Peripheral Actions

In addition to its desirable central actions, clomiphene can exert less desirable
antiestrogenic effects at peripheral sites in the reproductive system, which some have
suggested might explain the difference between ovulation and pregnancy rates achieved
with clomiphene treatment. Adverse effects of clomiphene on the endocervix, the
endometrium, the ovary, the ovum, and the embryo have been described, but there
is no compelling evidence to indicate that such effects have important clinical
consequences in most women.

On balance, the weight of evidence from controlled trials suggests that the quality
and quantity of cervical mucus production can be decreased in clomiphene treatment
cycles. Whereas some have observed no significant changes in mucus characteristics
during treatment,42 others have found clomiphene has dose-dependent adverse
effects.43,44 The conflicting results have several possible explanations. The effect may
be more apparent when the interval between the end of treatment and ovulation is
short.43 The effect might often be negated by higher serum estradiol levels resulting from
clomiphene-induced multifollicular development.45 It also is possible that some
individuals may be more sensitive to the effect.46 Regardless, any adverse effect that
clomiphene may have on cervical mucus does not prevent pregnancy (Chapter 25). In
recent years, even the evaluation of cervical mucus has all but disappeared from
clinical practice because controlled trials have demonstrated that postcoital testing (the
traditional test of cervical factors) has little or no predictive value47,48 and because
modern advanced treatment regimens for persistent infertility now routinely incorporate
intrauterine insemination (IUI), which bypasses the cervix altogether.49,50

Impaired endometrial growth also has been reported in clomiphene-treated
women. However, preovulatory endometrial thickness in clomiphene-induced cycles
remains well within the range normally observed in spontaneous ovulatory cycles in the
large majority of women.49,51,52,53,54,55,56 Other subtle differences in endometrial
morphology have been attributed to the effects of clomiphene, but their clinical
relevance, if any, is uncertain.57,58 It is likely that clomiphene inhibits endometrial
growth, at least in some women, for the same reasons that it may inhibit cervical mucus
production, but the same caveats apply; the effect is inconsistent, may be offset by the
higher estrogen levels in clomiphene-induced cycles, and probably has little clinical
importance, except perhaps in those individuals exhibiting grossly poor endometrial
growth (peak preovulatory thickness <5–6 mm).

Clomiphene does not appear to have any clinically relevant direct effects on the
ovary or embryo. Although clomiphene can inhibit steroid hormone production by

cultured avian,59 ovine,60 and human granulosa/luteal cells in vitro,61 serum estrogen
and progesterone concentrations in clomiphene-induced cycles are typically higher, not
lower, than in spontaneous ovulatory cycles. Adverse effects on mouse ovum
fertilization and embryo development have been observed in vitro,62 but studies in
women indicate that serum concentrations of enclomiphene and zuclomiphene never
approach the levels required to induce such effects, even after several consecutive
treatment cycles.35

Clinical Indications

Before the introduction of aromatase inhibitors, and large randomized controlled trials
demonstrating higher live birth rates with letrozole, clomiphene citrate was the
traditional drug of choice for ovulation induction in anovulatory infertile women with
normal thyroid function, normal serum prolactin levels, and normal endogenous estrogen
production, as determined by clinical observations (oligomenorrhea, estrogenic
cervical mucus), a serum estradiol determination (> approximately 40 pg/mL), or a
normal menstrual response to a progestin challenge (WHO Group II).63,64 Although the
drug also frequently is used empirically to stimulate multifollicular development in
ovulatory women with unexplained infertility (in combination with IUI),50,65,66,67,68 the
focus here is on ovulation induction in anovulatory women; empiric clomiphene and
other treatments for unexplained infertility are discussed in detail in Chapter 25.

Given its mechanism of action, it is not surprising that clomiphene typically is
ineffective in women with hypogonadotropic hypogonadism (WHO Group I).
Together, low or low-normal FSH levels and low serum estrogen concentrations
indicate that the hypothalamic-pituitary-ovarian axis is not functioning normally in
women with hypothalamic amenorrhea; if it were, FSH levels would be high because
estrogen concentrations are low. If low endogenous estrogen concentrations cannot
stimulate increased FSH secretion, there is little reason to think that a clomiphene-
induced decrease in the level of negative estrogen feedback will succeed, and it rarely
does. Alternative treatments that directly stimulate the pituitary (pulsatile exogenous
GnRH) or the ovary (exogenous gonadotropins) usually are required.

Because the corpus luteum derives from the ovulatory follicle, its functional
capacity depends, in part, on the quality of preovulatory follicular development.
Logically, inadequate follicular development can be expected to cause or predispose to
poor luteal function, if ovulation still occurs. Indeed, the most obvious example of poor
luteal function, a short luteal phase, is associated with abnormally low follicular phase
FSH levels.69,70 Consequently, clomiphene could be both a logical and effective choice
for treatment.71,72,73,74 Progesterone levels typically are higher in clomiphene-induced
ovulatory cycles than in normal spontaneous cycles, likely because preovulatory
follicular development is optimized and because treatment often results in more than one
corpus luteum.74,75

Clomiphene citrate treatment is generally limited to women with demonstrated
ovulatory dysfunction but has also been offered to normally ovulating women whose
infertility remains unexplained, particularly when they are young and infertility is of
short duration, and those unwilling or unable to pursue more aggressive treatments. The
putative efficacy of clomiphene treatment in women with unexplained infertility has

been attributed to optimizing follicular development or to the “superovulation” of more
than a single ovum. However, clomiphene alone does not seem to significantly improve
live birth rates or time to pregnancy compared to expectant management in unexplained
infertility.65 Empiric clomiphene treatment for unexplained infertility is most

effective when combined with IUI, in an effort to increase the numbers of both ova
and sperm (Chapter 25).50,65,76 On the contrary, in anovulatory women with PCOS

treated with clomiphene, IUI is not superior to timed intercourse, when the semen
analysis is within the normal range.77

Clomiphene Treatment Regimens

Clomiphene is administered orally, typically beginning on the third to fifth day after the
onset of a spontaneous or progestin-induced menses. Ovulation and conception rates and
pregnancy outcomes are similar when treatment starts anywhere between cycle days 2
and 5.78 In women with amenorrhea, treatment can begin immediately, without inducing
endometrial shedding, if pregnancy has been excluded. Indeed, available evidence
suggests that progestin-induced endometrial shedding is associated with a longer
treatment cycle, lower conception and live birth rates, and longer time to pregnancy.79,80
The dose of clomiphene required to induce ovulation correlates with body weight but
cannot be predicted confidently for an individual woman.81,82 Although obese women
often require higher doses of clomiphene treatment, the results achieved ultimately are
similar to those observed in lean women.83,84 No clinical or laboratory parameter has
proven utility for predicting the dose of clomiphene needed to induce ovulation (Figure
27.2).81,84

FIGURE 27.2

Treatment usually starts with a single 50-mg tablet daily for a 5-day interval and, if
necessary, increases by 50 mg increments in subsequent cycles until ovulation is
achieved. Most women who respond to clomiphene will respond to either 50 mg
(52%) or 100 mg (22%).85,86 Lower doses (12.5–25 mg daily) deserve consideration
for women who prove highly sensitive to the drug or develop large ovarian cysts that
prevent continued treatment.87 Although not approved by the U.S. Food and Drug
Administration, higher doses of clomiphene (150–250 mg daily) sometimes can succeed
when lower doses fail (150 mg, 12%; 200 mg 7%; 250 mg 5%).85,86 We believe that
treatment with doses up to 150 mg is reasonable before considering alternatives and
recommend against the use of higher doses.85 Longer durations of clomiphene treatment
(7–10 days) can succeed in some women when standard treatment does not and
occasionally may be useful when there are no practical alternatives.82,88,89

The same methods used for diagnosis of anovulation can be used to evaluate the
response to treatment. BBT recordings are simple and inexpensive but can become
tedious over time. A serum progesterone level greater than 3 ng/mL provides
reliable evidence that ovulation has occurred4,5 but must be timed appropriately for
confident and correct interpretation. Measuring the serum progesterone concentration
between cycle days 22 and 25 will minimize the risk of sampling immediately after
ovulation (occurring as late as cycle day 19–20 in cycles lasting up to 35 days) or
before menses, when levels less than 3 ng/mL might be observed and misinterpreted.
More sophisticated tests of ovulation involving greater costs and logistical demands are
unnecessary to determine only if ovulation occurred but may be justified once successful
ovulation induction has been achieved.

Commercial test kits can detect the midcycle urinary LH surge and help to determine
not only whether ovulation occurred, but when, and to accurately define the length of the
luteal phase.90 In clomiphene-induced ovulatory cycles in anovulatory women, the
LH surge typically occurs 5–12 days after treatment ends, most often on cycle day
16 or 17 when clomiphene is administered on days 5–9.91 Ovulation generally occurs
14–26 hours after surge detection and almost always within 48 hours.90 However, in
clinical practice, both false-negative and false-positive results are relatively
common.92,93 An endometrial biopsy yielding secretory endometrium also implies recent
ovulation,94 but the associated costs and discomfort cannot be justified for that purpose
alone. Serial transvaginal ultrasonography can demonstrate the size and number of
developing follicles, track endometrial growth, and provide presumptive evidence of
ovulation95,96 but is difficult to justify when less complicated and costly methods can

provide the necessary information. Some advocate monitoring at least the first cycle of
treatment to identify those who respond excessively.97 A study comparing fecundity in
clomiphene-induced cycles monitored with BBT, urinary LH excretion, or serial
transvaginal ultrasonography found no clear advantage for any one of the three
methods.98

Traditionally, when the serum progesterone concentration reveals persistent
anovulation after clomiphene treatment, a progestin is prescribed (e.g.,
medroxyprogesterone acetate, 5–10 mg daily for 5–7 days) to induce menses before the
next cycle begins at a higher dosage. Although effective, the sequence takes time and
several months may pass before a patient is proven unresponsive to clomiphene. A
“stair-step” treatment protocol is an alternative that can shorten the time required to
achieve ovulation and to identify those who require different treatment. The regimen
involves treatment with clomiphene (50 mg) on cycle days 5–9 after a spontaneous or
induced menses, ultrasonography on days 11–14, immediate treatment at the next higher-
dose level (100 mg) if no dominant follicle (≥15 mm) has emerged, repeated
ultrasonography 1 week later, and, if still no dominant follicle is observed, immediate
treatment at the highest dose level (150 mg) and ultrasonography again 1 week later.99
Stair-step protocol is associated with shorter time to ovulation, higher rate of ovulation,
and similar pregnancy rates, albeit with higher incidence of mild side effects.80,100,101

In the past, monthly pelvic examinations to exclude residual ovarian enlargement
were recommended before each new clomiphene treatment cycle began. It is still
prudent to postpone further treatment when symptoms lead to discovery of a large cyst
or grossly enlarged ovaries, but clinical studies and experience indicate that routine
baseline physical examination or ultrasonography is unnecessary.91 Nevertheless,
regular contact should be maintained to review the progress of treatment and to ensure
that any additional evaluation needed is accomplished efficiently.

Results of Clomiphene Treatment

Clomiphene will induce ovulation successfully in 70–80% of properly selected
women.102,103 The likelihood of response decreases with increasing age and body mass
index and with the extent of any associated hyperandrogenemia in anovulatory women.
Interestingly, women with amenorrhea are more likely to conceive than those with
oligomenorrhea,102 possibly because infertile women who menstruate also likely
ovulate, albeit infrequently, and are more likely to have other coexisting infertility
factors.

Among anovulatory infertile women who respond to clomiphene treatment, the
overall cycle fecundability is approximately 15%. In women with no other infertility
factors, cycle fecundability may reach as high as 22%, comparable to that observed in
normal fertile couples after discontinuation of barrier contraception and those with male
factor infertility receiving therapeutic donor inseminations.102 Cumulative pregnancy
rates of 70–75% can be expected over six to nine cycles of treatment.100,104
Thereafter, cycle fecundability falls substantially. When pregnancy is not achieved
within 3–6 clomiphene-induced ovulatory cycles, the infertility investigation should
be expanded to exclude other infertility factors not yet evaluated, or the overall
treatment strategy should be modified if evaluation is already complete. Prolonged
treatment with clomiphene is inappropriate, particularly for women over age 35.

Side Effects

Clomiphene treatment generally is very well tolerated. Minor side effects are relatively
common but rarely are persistent or severe enough to require that treatment be
discontinued.

Transient hot flashes, usually limited to the short interval of treatment, occur in 10–
20% of women.105 Considering that clomiphene causes a central misperception that
endogenous estrogen levels are low, vasomotor symptoms are not difficult to
understand. Other mild and less common side effects include headache, breast
tenderness, pelvic pressure or pain, and nausea (2–5%). Visual disturbances (blurred or
double vision, scotomata, light sensitivity) are uncommon (1–2%) and reversible, but
reports of persistent “afterimages” (palinopsia) and light sensitivity (photophobia) make
them nonetheless unnerving106; when such symptoms appear, prudence dictates that
treatment be abandoned in favor of alternative methods for ovulation induction.

Risks

Clomiphene treatment has risks, but serious complications are rare. Inevitably,
questions arise concerning the risks for multiple pregnancy, congenital anomalies, and
other potential adverse outcomes associated with clomiphene treatment.

The principal risk associated with clomiphene treatment is an increased risk for
conceiving a multiple pregnancy. The clomiphene-induced increase in FSH secretion
is only transient, so normal selection mechanisms still operate to yield only a single
mature follicle in most treatment cycles in anovulatory women. Nevertheless,
multifollicular development is relatively common and the overall risk of multiple
pregnancy is increased to approximately 7–10%.107,108,109 The large majority of
multiple pregnancies conceived in clomiphene-induced cycles are twins; the risk for
triplets is 0.3–0.5%, for quadruplets 0.3%, and for quintuplets 0.1%.29,110 The higher
risk of multifetal gestation is another reason to treat with the lowest effective dose
of clomiphene; higher doses do not improve results and only increase the risk of
superovulation and multiple pregnancy, with all of the attendant antenatal and
neonatal complications.

There is no evidence that clomiphene treatment increases the overall risk of
birth defects or of any one anomaly in particular.111 Several large series have
examined the question and have drawn the same conclusion.107,108,109,111,112 In a series of
1,034 pregnancies resulting from clomiphene treatment, 14.2% ended in miscarriage,
0.5% in ectopic pregnancy, 0.1% in molar pregnancy, and 1.6% in stillbirth, and among
935 live born infants, malformations were detected in 21 (2.3%).111 Earlier suggestions
that the risk of neural tube defects might be higher in pregnancies conceived after
clomiphene treatment were not confirmed in later investigations.113,114 A small study of
pregnancy outcomes in women exposed inadvertently to clomiphene during the first
trimester of pregnancy found no evidence of teratogenicity.115 There also is no evidence
that clomiphene treatment increases the risk of developmental delay or learning
disability in children conceived during clomiphene treatment.116

Early studies suggested that the incidence of spontaneous miscarriage in
pregnancies resulting from clomiphene treatment might be increased, but a number of
others have observed miscarriage rates no different from those in pregnancies
conceived without treatment.85,100,104,117,118

The incidence of ovarian hyperstimulation syndrome (OHSS) in clomiphene-
induced cycles is difficult to determine confidently because definitions of the syndrome
vary widely among studies. In general, mild symptoms of ovarian hyperstimulation
(transient abdominal discomfort, mild nausea, vomiting, diarrhea, and abdominal

distention) are not altogether uncommon but require only expectant management. When
induction of ovulation proceeds in the recommended incremental fashion to establish the
minimum effective dose, the risk of clinically significant OHSS (massive ovarian
enlargement, progressive weight gain, severe abdominal pain, intractable nausea and
vomiting, gross ascites, oliguria) is remote.

The incidence of ovarian cancer is decreased among parous women and those
using hormonal contraception for prolonged intervals, suggesting that “incessant
ovulation” (repeated epithelial disruption and repair) predisposes to the development of
ovarian cancer and that treatment with ovulation-inducing drugs might increase the
risk.119 The results of case-control studies conducted in the 1990s lent credence to the
notion and raised considerable concern,120,121 although their conclusions were
challenged because of important methodologic flaws. One study compared infertile
treated women to fertile women rather than to infertile untreated women, even though
infertility and nulliparity were known risk factors for ovarian cancer.120 Another
included cancers of all types and tumors of low malignant potential despite their
differing pathophysiology.121 Since then, numerous studies have confirmed that the
incidence of ovarian cancer is increased in infertile women but have failed to find any
substantive evidence that ovulation-inducing drugs increase the
risk,122,123,124,125,126,127,128,129,130,131,132 and a pooled analysis of results from eight case-
control studies found that fertility drug use among nulliparous subfertile women was
associated with an increased incidence of borderline serous ovarian tumors (OR = 2.43,
CI = 1.01−5.88) but not with any invasive cancers (OR = 1.60, CI = 0.90−2.87).133 In
2013, a large U.S. study including 9,825 women, with an average follow-up time of
17.6 years for ovarian cancer cases and 26.2 years for noncases, found that while ever
use of clomiphene was not associated with ovarian cancer, women who remained
nulligravid were found to have an increased risk of breast cancer with ever use of
clomiphene (RR = 3.63, 95% CI = 1.36–9.72).134

The results of studies of the risk for breast cancer have been conflicting, with some
showing no association with ovulation-inducing drugs and others suggesting possible
increases in risk in certain subgroups.128 A 2014 study including 9,892 women who
were evaluated for infertility with a median follow-up time of 30 years reported
unchanged risk of breast cancer with ever use of clomiphene (HR = 1.05; 95% CI =
0.90–1.22). However, receiving multiple cycles of clomiphene was associated with an
increased risk of invasive cancers (HR = 1.69; 95% CI = 1.17–2.46).135

A 2017 meta-analysis reported a positive association between clomiphene exposure
and endometrial cancer among subfertile women (RR = 1.32; 95% CI = 1.01–1.71;
very low-quality evidence), although only at high dosage (RR = 1.69, 95% CI = 1.07–
2.68) and at a high number of cycles (RR = 1.69, 95% CI = 1.16–2.47). However,

whether the association is due to the underlying conditions requiring clomiphene or the
drug itself is uncertain.136

Overall, the available data are quite reassuring. No causal relationship between
ovulation-inducing drugs and ovarian, breast, or endometrial cancer has been
established, but prolonged treatment with clomiphene nonetheless should be
avoided, primarily because it has little hope of success.

Adjuvant and Combination Treatments

Clomiphene resistance describes women who do not ovulate in response to clomiphene
treatment, not those who fail to conceive despite successful clomiphene-induced
ovulation. In the latter group, additional evaluation is indicated to identify other
potential coexisting infertility factors not already excluded. If or when that has been
accomplished, persistent infertility is best regarded and treated as unexplained
infertility (Chapter 25).

Although most properly selected women will ovulate in response to clomiphene
treatment, many do not. Direct ovarian stimulation with exogenous gonadotropins,
discussed later in detail, is an obvious alternative, but it is by no means the only option
that merits consideration. Many clomiphene-resistant anovulatory infertile women will
respond to supplemental or combination treatment regimens. Options include adjuvant
treatment with glucocorticoids, exogenous human chorionic gonadotropin (hCG), or
metformin and preliminary suppressive therapy (hormonal contraceptives). It is helpful
to be familiar with these less common ovulation induction strategies because many
couples are understandably reluctant or unable to pursue the obvious alternative of
gonadotropin treatment once fully advised of the associated costs, logistical
demands, and risks.

Failure to respond to one or more of these less commonly employed treatment
regimens is not a prerequisite for exogenous gonadotropin therapy. They are simply
useful alternatives for those unwilling or unable to pursue gonadotropin therapy and, for
some, may be the only option when clomiphene treatment has failed. A choice among
them is not entirely arbitrary but should consider specific elements of the patient’s
history, the results of laboratory evaluation, and observations in previous unsuccessful
clomiphene treatment cycles.

Clomiphene and Glucocorticoids

Numerous studies have examined the efficacy of adjuvant treatment with glucocorticoids
in clomiphene-resistant anovulatory women, and all have found that combined treatment
with clomiphene and a glucocorticoid can successfully induce ovulation in many who
fail to respond to clomiphene alone.89,137,138,139,140,141 Both continuous and more limited
follicular phase treatment regimens (cycle days 5–14) have been described, using either
prednisone (5 mg daily) or dexamethasone (0.5–2.0 mg daily). Whereas some studies
have suggested that combined treatment with clomiphene and glucocorticoids is most
effective in women having elevated serum dehydroepiandrosterone sulfate (DHEA-S)
concentrations,137,138 others have found that treatment also can be effective in those with
normal DHEA-S levels139,141 and in unselected populations of clomiphene-resistant

women.89,140,142

In the largest randomized trial involving more than 200 clomiphene-resistant
anovulatory infertile women, over 80% of those receiving combined treatment with
clomiphene (200 mg daily, cycle days 5–9) and dexamethasone (2 mg daily, cycle days
5–14) ovulated, compared to 20% of controls treated with clomiphene and placebo; the
cumulative pregnancy rate in women receiving dexamethasone (40%) was 10-fold
higher than in those who received placebo (4%).141 The mechanism of glucocorticoid
action remains unclear but appears to involve more than simple androgen suppression.
Other possibilities include direct effects on the developing oocyte and indirect effects
on intrafollicular growth factors and cytokines, which may act synergistically with
FSH.143 Regardless, adjuvant treatment with glucocorticoids may be justified for three
to six cycles when it is successful but should be promptly discontinued when it is not.
There is no evidence that glucocorticoid treatment has any important side effects or
risks when used in the doses and durations described.

Clomiphene and HCG

Although there are few if any data to demonstrate its value, exogenous hCG has been
used commonly as a surrogate LH surge to trigger ovulation in clomiphene-induced
cycles, particularly when IUI is performed, as in couples with unexplained infertility
and those with a coexisting male factor. Adjuvant hCG treatment can be useful but has
limited indications, distinct disadvantages, and potential consequences.

In anovulatory women who fail to ovulate in response to clomiphene alone,
adjuvant hCG treatment is based on the premise that clomiphene may be successful in
stimulating the emergence of a preovulatory follicle but ultimately fail to trigger an
endogenous LH surge and to induce ovulation. Physiologically, and in practice, the
scenario is unlikely. Moreover, serial transvaginal ultrasonography is required to
demonstrate the phenomenon and to ensure that the ovulatory stimulus is delivered at the
appropriate time. If administered blindly and prematurely, before the dominant follicle
is mature enough to respond, hCG is more likely to induce atresia than ovulation.

The question of when to administer hCG presents a dilemma. Although hCG
commonly is administered when the lead follicle reaches 18–20 mm,144 clinical studies
indicate that the peak preovulatory follicular diameter in successful clomiphene-induced
ovulatory cycles ranges between 18 and 30 mm (mean 25 mm).91,145,146 Considering that
the preovulatory follicle grows approximately 2 mm/day as it approaches maturity,95,96
the corresponding interval may thus span up to 6 days. Normally, the preovulatory
follicle triggers its own ovulatory stimulus at the peak of maturity by generating and
maintaining the estrogen levels that are required to induce the LH surge. The timing of

the spontaneous LH surge is therefore always optimal, but that of hCG treatment can
never be more than an educated guess.

When combined treatment with clomiphene and IUI is required, insemination
usually is best performed on the day after detection of the spontaneous LH surge,
using one of the now widely available commercial kits designed for the purpose,
because ovulation generally occurs 14–26 hours after urinary LH surge
detection.90,147 However, the lower limit of LH detection usually is between 20 and 40
IU/L, and many ovulatory women exhibit peak LH levels below 40 IU/L or surges of
brief duration that may escape detection92; false-negative results are therefore not
uncommon and frustrating. Exogenous hCG can be useful for the few women who
require IUI but repeatedly fail to detect the LH surge despite other objective
evidence of successful ovulation induction. In such circumstances, we believe that
hCG is best postponed until the preovulatory follicle reaches or exceeds 20 mm in mean
diameter. Ovulation occurs 34–46 hours after hCG injection,148 so IUI usually is
performed approximately 36 hours later.

When the LH surge can be detected, adjuvant hCG treatment has no value and
only adds unnecessary expense and inconvenience. A 2014 meta-analysis including
two randomized controlled trials where anovulatory women undergoing ovulation
induction with clomiphene citrate were given an ovulatory dose of hCG or not reported
similar live birth, ovulation, pregnancy, and miscarriage rates.149 Another meta-analysis
including seven studies comparing hCG trigger with LH monitorization for timing IUI
for women who were treated with clomiphene reported significantly lower pregnancy
rates in the hCG group.150 The idea that hCG may still serve to ensure or improve the
quality of luteal function even if it is not required to trigger ovulation also is not
supported by existing data. In spontaneous ovulatory cycles, hCG treatment
superimposed on the endogenous LH surge has no effect on luteal phase duration or
serum estrogen or progesterone concentrations151; the same is true in clomiphene-
induced ovulatory cycles.152 In sum, adjuvant hCG treatment is best limited to those few
women who require IUI and ovulate but cannot reliably detect a midcycle LH surge.

Clomiphene and Metformin

Insulin resistance and hyperinsulinemia are common features of PCOS and an important
contributing cause of the hyperandrogenism and chronic anovulation that characterize
the disorder. Anovulatory infertile women with PCOS and hyperinsulinemia also are
typically more resistant to clomiphene treatment.

Recognition of the pathophysiologic importance of insulin resistance in PCOS
stimulated intense interest in the use of insulin-sensitizing agents for the treatment of the

disorder. Metformin is a biguanide oral insulin-sensitizing agent that acts primarily by
reducing hepatic gluconeogenesis but also decreases intestinal absorption of glucose
and increases peripheral glucose uptake and utilization. The effects of metformin on
insulin levels and sensitivity, androgen concentrations, and other metabolic and clinical
measures are considered at length elsewhere in this text (Chapter 11); its adjunctive use
an ovulation-inducing agent is the focus here.

Treatment with metformin alone or with other insulin-sensitizing drugs
(thiazolidinediones, D-chiro-inositol) can increase ovulation rates in some women with
PCOS,153,154,155,156,157 but there is no practical method for predicting those who will
respond. The literature is mostly populated with small studies that include
heterogeneous groups of patients, which vary in their BMI, insulin resistance (which has
not been tested at all or tested using different methodologies), and prior treatment status
(i.e., clomiphene resistant or treatment naïve). Moreover, different treatment regimens
with regard to timing and dose have been employed across these studies. Finally, live
birth rate, the most important outcome of treatment, has not been reported in many. As
can be expected, results from such studies are often heterogeneous preventing reliable
pooling of their data. As such, assessment of the role of metformin and other insulin
sensitizers as adjuvants for ovulation induction is difficult, despite years of research.157

In the largest randomized trial, 626 women with PCOS from the United States with
oligomenorrhea and hyperandrogenism and a mean BMI greater than 34 kg/m2 were
treated with clomiphene, metformin, or both.118 Ovulation and live birth rates were
significantly higher with clomiphene alone compared with metformin (49% vs. 29% and
22.5% vs. 7.2%, respectively; P < 0.001). Addition of metformin did not significantly
improve outcomes compared to clomiphene alone.

A 2017 meta-analysis evaluated the effectiveness and safety of insulin-sensitizing
drugs in improving reproductive outcomes for women with PCOS undergoing ovulation
induction and concluded that metformin is associated with significantly higher rates of
ovulation, clinical pregnancy, and live birth rates compared to placebo or no
treatment.156 However, the analysis for live birth rate included four trials with a total of
435 women and demonstrated only a marginal benefit with an odds ratio of 1.59 (CI =
1.0–2.51). When clomiphene was compared to metformin, live birth rates were similar
between the groups (OR = 0.71, CI = 0.49–1.01), but data were very low quality and
were found to be inconclusive and inconsistent. In subgroup analysis by obesity status,
data from the nonobese group showed a possible benefit from metformin for live birth
(OR = 1.71, 95% CI = 1.00–2.94) and pregnancy (OR = 1.56, 95% CI = 1.05–2.33) rate
and no clear difference in ovulation rates (OR = 0.81, 95% CI = 0.51–1.28).
Surprisingly, obese women treated with metformin had a lower ovulation (OR = 0.29,
95% CI = 0.20–0.43), clinical pregnancy (OR = 0.34, 95% CI = 0.21–0.55), and live

birth (OR = 0.30, 95% CI = 0.17–0.52) rate, compared to clomiphene. The same meta-
analysis also concluded that combined treatment with metformin and clomiphene
achieves higher ovulation (OR = 1.57, CI = 1.28–1.92) and pregnancy rates (OR = 1.59,
CI = 1.27–1.99), compared to treatment with clomiphene alone.156 There was no
conclusive evidence that combined treatment with metformin and clomiphene can
increase live birth rates over those achieved with clomiphene alone (OR = 1.21, CI =
0.92–1.59). The results for combined therapy did not vary across subgroups based on
obesity status. The attempt in combining the two medications can be justified for women
having few alternatives besides ovarian drilling or treatment with exogenous
gonadotropins. Indeed, a sensitivity analysis based on six studies including clomiphene-
resistant women showed a more pronounced increase in ovulation rate (OR = 4.89, CI =
2.62–9.13). However, clomiphene resistance was defined differently in all primary
trials.

Limited evidence indicates that combined treatment with metformin and
roziglitazone,158 or with clomiphene and rosiglitazone,159 is no more effective than
metformin alone. Combined with the safety alert issued by the U.S. Food and Drug
Administration concerning a possible increased risk of ischemic cardiovascular events
in patients receiving treatment with thiazolidinediones,160 these data argue against their
adjuvant use for ovulation induction. In summary, combined treatment with
metformin and clomiphene deserves consideration in women who prove to be
clomiphene resistant.

A 2010 randomized trial compared combined treatment with metformin and
clomiphene with aromatase inhibitors in 250 clomiphene-resistant women.161
Combination treatment involved 500 mg metformin 3 times daily for 6–8 weeks
followed by 150 mg/day clomiphene for 5 days. Despite significantly higher ovulation
rates with clomiphene-metformin than with letrozole (69.6% vs. 64.9%), clinical
pregnancy rates were similar between groups (14.4% vs. 14.7%).

Metformin treatment is commonly associated with gastrointestinal side effects
including nausea, vomiting, abdominal cramps, and diarrhea that can be severe enough
to limit the dose administered or require discontinuation of treatment.162,163,164,165
Because side effects tend to be dose-dependent and diminish with time, it is usually best
to begin with a low daily dose (500 mg), increasing gradually at weekly intervals to a
daily dose of 1,500–2,000 mg, as tolerance allows. Lactic acidosis can be a rare
complication of metformin treatment, although recent systematic reviews have
questioned whether there is a true causal relationship.166,167 Women at highest risk are
those with chronic hypoxemic conditions related to cardiovascular, renal, hepatic, and
pulmonary disease and advanced age.

Although some have advocated metformin treatment to reduce the increased risk for

miscarriage in women with PCOS,168,169,170 available data suggest otherwise.
Miscarriage rates were similar between women treated with metformin compared to no
treatment and between women treated with metformin compared to clomiphene; women
who received combination therapy with metformin and clomiphene had significantly
higher rates of miscarriage than women who received clomiphene alone (OR = 1.59, CI
= 1.03–2.46). Metformin treatment during pregnancy also has been advocated to reduce
the risk for developing gestational diabetes and other pregnancy complications in
women with PCOS.171,172 In diabetic women, treatment with metformin during
pregnancy has been associated with an increased prevalence of preeclampsia and
increased perinatal mortality in some studies,173 but not in others.174,175 Therefore,
although there is no evidence that metformin treatment during pregnancy is associated
with any increased risk for major fetal malformations,176 and metformin is currently
classified as U.S. Food and Drug Administration pregnancy category B, routine
metformin treatment during pregnancy is not recommended for women with PCOS.

Preliminary Suppressive Therapy

Considering that anovulation reflects a dysfunctional hypothalamic-pituitary-ovarian
axis, it is reasonable to think that an interval of preliminary suppressive therapy might
help to restore harmony and ovulatory function, at least temporarily. The idea is
consistent with clinical observations of a few normal menstrual cycles immediately
following discontinuation of estrogen-progestin contraception in some women who
previously exhibited abnormal menstrual patterns. Limited data suggest that a 2-month
interval of continuous estrogen-progestin contraception can effectively suppress serum
LH and androgen levels and that ovulation rates up to 70% and cumulative pregnancy
rates over 50% can be achieved with clomiphene treatment immediately thereafter in
women who were previously clomiphene resistant.177,178

A long-acting GnRH agonist, alone or in combination with an estrogen-progestin
contraceptive, can be used for the same purpose. Combined suppressive therapy with a
GnRH agonist and an estrogen-progestin contraceptive (3–6 months) achieves a greater
and longer-lasting reduction in serum LH and androgen concentrations than treatment
with estrogen-progestin contraception alone and also prevents the otherwise inevitable
estrogen deficiency symptoms associated with the use of a GnRH agonist. Spontaneous
resumption of ovulatory cycles can follow,179,180,181 potentially eliminating even the
need for clomiphene treatment. GnRH antagonists would likely have a similar effect and
allow the use of oral medication.

AROMATASE INHIBITORS

Aromatase inhibitors, which were used primarily in the treatment of postmenopausal
breast cancer, emerged as a new class of ovulation-inducing agents. Even though the use
of aromatase inhibitors for ovulation induction has been controversial since their first
introduction in 2001,182 letrozole is now considered the first-line therapy for ovulation
induction in women with PCOS,183 as it provides significantly higher live birth rates
compared to clomiphene.184

Pharmacology and Mechanism of Action

Anastrozole and letrozole are triazole (antifungal) derivatives that act as potent,
competitive, nonsteroidal inhibitors of aromatase,185,186 the enzyme that catalyzes the
rate-limiting step in estrogen production. They block estrogen production both in the
periphery and in the brain, resulting in a compensatory increase in pituitary
gonadotropin secretion that stimulates ovarian follicular development.187,188,189 In this
regard, their mechanism of action is similar to, but also distinct from, that of
clomiphene. Although both stimulate increased gonadotropin secretion by decreasing the
negative feedback effects of estrogen during treatment, clomiphene does so via
depletion of central estrogen receptors, whereas aromatase inhibitors decrease estrogen
production directly (Figure 27.3).

FIGURE 27.3

At least in theory, the different actions of aromatase inhibitors and clomiphene may have
functional, and clinical, importance. Lower estradiol levels and higher luteal phase
progesterone levels attained in letrozole-stimulated cycles than clomiphene-stimulated
cycles may be the mechanism behind higher live birth rates with letrozole.22
Gonadotropin secretion is anticipated to promptly decrease due to negative feedback by
rapidly rising estrogen production by growing follicles following the cessation of
aromatase inhibitor. To the contrary, the lack of immediate negative feedback following
cessation of clomiphene, due to the depletion of central estrogen receptors, results in a
more sustained increase in gonadotropin levels that is more likely to support
multifollicular development. However, number of growing follicles and mono-ovulatory
cycles are similar between women stimulated with clomiphene and letrozole.190
Likewise, multiple pregnancy rates are also at least as low in letrozole as in
clomiphene-induced cycles.184 The transient accumulation of androgen substrate during
treatment with aromatase inhibitors also may increase FSH receptor expression191,192

and production of insulin-like growth factor-1 (IGF-1),193,194,195 amplifying the actions
of FSH.

Peripheral Actions

Despite lower serum estradiol levels in letrozole-stimulated cycles than in clomiphene-
stimulated cycles, letrozole could have been expected to have less of an adverse effect
on endometrial growth, since it does not block estrogen receptors. Indeed, a 2018
systematic review comparing the effect of clomiphene citrate and other ovulation
induction drugs on endometrial thickness in women with WHO group 2 anovulation
reported significantly higher endometrial thickness in letrozole-induced cycles (15
RCTs, 1,957 women, 3,892 cycles; weighed mean difference, 1.39 mm; 95% CI = 2.27–
0.51).196 However, the results in individual studies demonstrated high heterogeneity and
comprise low-quality evidence. Whether the effect of letrozole on endometrial thickness
has a significant effect on treatment outcome in terms of pregnancy and live birth rates is
controversial. Few studies investigated molecular markers or endometrial growth and
receptivity in letrozole-stimulated cycles. In general, letrozole was found to be
associated with a more favorable molecular profile than clomiphene.197 Clomiphene is
associated with significantly decreased protein expression of active B-catenin, inactive
glycogen synthase kinase-3 beta, and estrogen receptor 1.198 A retrospective study
involving women undergoing IVF reported increased integrin ανβ3 expression
following stimulation with letrozole.199 However, whether integrin expression is
different between letrozole- and clomiphene-stimulated cycles is controversial.200

Limited data suggest that letrozole does not have a clinically relevant direct effect
on oocytes or embryos. In a mouse model of PCOS, superovulation with letrozole was
not found to affect meiotic spindle assembly or blastocyst development, compared with
FSH-stimulated superovulation.201

Clinical Indications

Following publication of large randomized controlled trials demonstrating higher live
birth rates with letrozole than with clomiphene, it is now regarded the drug of choice for
ovulation induction in anovulatory infertile women with PCOS.183 The drug has also
been tested in ovulatory women with unexplained infertility (in combination with
IUI).202

Similar to clomiphene, letrozole is ineffective in women with hypogonadotropic
hypogonadism (WHO Group 1), who already have low serum estrogen concentrations
and a dysfunctional hypothalamic-pituitary-ovarian axis.

Despite evidence of effectiveness and safety in well-designed large randomized
controlled trials, letrozole is still used off-label for ovulation induction in the United
States, since it has not been approved by the U.S. Food and Drug Administration (FDA)
for this indication.

Aromatase Inhibitor Treatment Regimens

In almost all studies conducted to date, letrozole (2.5–7.5 mg daily) and anastrozole (1
mg daily) have been administered for a 5-day interval. Early on, a phase II randomized
controlled trial comparing a single-dose therapy with anastrozole and 5-day course of
clomiphene reported significantly lower ovulation rates with anastrozole and the
sponsoring company stopped the development of the drug.203 Thus, letrozole is the most
studied and the most commonly used aromatase inhibitor in ovulation induction.

Letrozole is administered orally, typically beginning on the third to fifth day after
the onset of a spontaneous or progestin-induced menses. Ovulation and conception rates
and pregnancy outcomes are similar when treatment starts anywhere between cycle days
3 and 5.204 In women with amenorrhea, treatment can begin immediately, without
inducing endometrial shedding; however, pregnancy must be excluded. The starting dose
for letrozole is 2.5 mg a day for 5 days. If 2.5 mg/day fails to induce ovulation, the
dosage can be increased by 2.5 mg increments up to a maximum of 7.5 mg/day for 5
days. Despite the absence of published evidence with letrozole, dose increments can be
done in the same cycle without inducing bleeding, like the stair-step protocol with
clomiphene.99 One trial comparing outcomes achieved with 5 or 10 days of letrozole
treatment (5 mg and 2.5 mg daily, beginning on cycle day 1, respectively) in
clomiphene-resistant women (100 mg daily) observed significantly more preovulatory
follicles (3.0 vs. 1.8) and higher pregnancy rates (17.4% vs. 12.4%) in women
receiving the longer course of treatment.205

The same methods used for diagnosis of a spontaneous or clomiphene-induced
ovulation can be used to determine the response to letrozole. Whether monitoring and
triggering of ovulation is necessary and improves results over that achieved without
monitoring and fertility-oriented intercourse is controversial. However, it may be
prudent to monitor during the follicular phase of the first cycle to confirm ovulation or
to allow timely dose increments to achieve ovulation.

Results of Treatment with Aromatase Inhibitors

Several trials have compared letrozole and clomiphene in anovulatory women without
documented clomiphene resistance. The largest involved 750 patients who were
randomized to receive letrozole (2.5 mg daily increased up to a maximum of 7.5 mg/day
in case of anovulation) or clomiphene (50 mg daily increased up to a maximum of 150
mg/day), without ovulation trigger, up to five treatment cycles. In the letrozole group, a
significantly higher proportion of women achieved ovulation (88.5% vs. 76.6%, RR =
1.16; 1.08–1.24), and the proportion of ovulations over total treatment cycles was
significantly higher (61.7% vs. 48.3%, RR = 1.28; 1.19–1.37). Cumulative pregnancy
(27.3% vs. 21.5%) and live birth (27.5% vs. 19.1%, RR = 1.44; 1.10–1.87) rates were
also significantly higher with letrozole treatment.22 One randomized trial, which
recruited 100 anovulatory women with PCOS who had never received ovulation
induction, also reported significantly higher ovulation (60% vs. 32%) and a
nonsignificant increase in pregnancy rate (26% vs. 14%) with letrozole (5 mg/day) than
clomiphene (100 mg/day).206 A 2018 systematic review reported significantly higher
live birth rates with letrozole than clomiphene (OR = 1.79; 1.42–2.25).184 The
beneficial effect of letrozole seems independent of body mass index, that is, despite
decreasing overall live birth rates with increasing BMI, letrozole outperforms
clomiphene across categories of BMI.22,184 Miscarriage per pregnancy (OR = 0.96;
0.65–1.42) and multiple pregnancy rates (OR = 0.61; 0.41–1.16) are also similar
between letrozole- and clomiphene-induced cycles.184 Available evidence suggests
that letrozole should be considered the first-line agent for ovulation induction in
anovulatory women with PCOS.

In an early proof of concept trial involving anovulatory clomiphene-resistant
women, 9/12 of patients (75%) ovulated after treatment with letrozole (2.5 mg daily)
and hCG (lead follicle > 20 mm), three conceived (resulting in two singleton births),
and normal endometrial proliferation was observed in all.182 Aromatase inhibitors can
also be effective in anovulatory women who fail to ovulate in response to
clomiphene treatment.

Aromatase inhibitors also might be considered for women who respond to
clomiphene but exhibit grossly poor endometrial proliferation. Indeed, letrozole is
associated with a significantly thicker endometrium; however, the mean difference is
small at 1.39 mm (95% CI = 2.27–0.51).196 All studies have included monitoring with
ultrasonography and the vast majority used adjuvant treatment with hCG, so it is
unclear whether these additions to the treatment regimen are necessary to achieve
success. If not, the substantially lower complexity, risks, and costs of treatment,
compared to the alternative of gonadotropin therapy, make it easy to justify a trial