If hyperprolactinemia is evident, any secondary causes such as
medications are investigated. Certain antipsychotics, antihypertensives, or
antidepressants can increase prolactin levels and should be discontinued and
replaced with agents that do not increase prolactin. If the underlying cause cannot be
addressed, a dopamine agonist may restore testicular function and sperm
T.R.’s husband’s medical history does not support an identifiable cause of altered
sperm production or function. He does not report any signs of sexual dysfunction or
take medications that may negatively affect libido or erectile or ejaculatory function.
All components of the semen analysis are above the lower limit defined by the World
Health Organization. His normal physical examination and medical history also
support a lack of identifiable male causes of infertility. In this case, the extensive
testing of both T.R. and her husband has revealed no obvious contributor to
CASE 48-1, QUESTION 7: The couple completes their evaluation and is diagnosed with unexplained
infertility. What is the initial approach to treatment?
The diagnosis of unexplained infertility, or no identifiable cause after evaluation,
accounts for up to 25% of cases.
19 The treatment approach is empiric but typically
incorporates medications to stimulate ovulation, often in conjunction with intrauterine
insemination or other infertility procedures, which are discussed later in the chapter.
Regardless of the treatment approach, all couples pursuing pregnancy are
encouraged to avoid tobacco, alcohol, and illicit substances, and limit caffeine
9 The female partner should take a daily supplement containing 400 to 800 mcg
of folic acid to reduce the risk of neural tube defects once pregnancy occurs.
chronic medications must be evaluated for potential safety issues during pregnancy
and discontinued or switched to a safer alternative. Patients are encouraged to
achieve and maintain a normal weight.
9 Recommendations pertinent to T.R. include
discontinuation of alcohol use, limited caffeine intake, and initiation of a daily
multivitamin with 400 to 800 mcg of folic acid. T.R. should also confirm plans for
monitoring her asthma symptoms during pregnancy. Albuterol use during pregnancy
will be continued, but the frequency of use will be monitored carefully.
There are two general treatment approaches to ovarian stimulation: “ovulation
induction” (OI) and “superovulation (SO).” The approach depends on a patient’s
underlying ovulatory function. Ovulation induction is utilized in patients who are not
ovulating to promote an ovulatory cycle. This method may be accompanied by timed
natural intercourse or the use of insemination procedures to achieve pregnancy.
Superovulation, or controlled ovarian stimulation (COS), incorporates many of the
same medications, but is appropriate for women who are already having ovulatory
cycles but are still experiencing infertility. Additionally, SO is appropriate for
infertility procedures where the development of multiple ovarian follicles is
desirable (Case 48-2). The general approach to medication use with both strategies
Anovulatory women with adequate ovarian reserve and no other treatable cause
are candidates for OI. This process is designed to mimic the hormonal patterns of the
normal menstrual cycle. Follicle-stimulating hormone guides the initial recruitment
and development of ovarian follicles early in the menstrual cycle. This is followed
by development of a dominant follicle and increased estradiol levels. The elevated
estrogen triggers the LH surge and the release of the ovum mid-cycle for fertilization
(Fig. 48-1). The goal of OI is the development of a single dominant follicle.
The choice of medications for OI is dictated by hypothalamic–pituitary–ovarian
function. With adequate hypothalamic function, an oral regimen of CC, which exhibits
estrogen agonist and antagonist activity, is often utilized first line. Clomiphene citrate
inhibits estrogen binding in the hypothalamus to stimulate release of GnRH and
pituitary gonadotropins and induce ovarian follicular development. Ovulation is
successful in approximately 75% of patients using CC.
are not approved by the US Food and Drug Administration (FDA) for OI, but also
increase release of GnRH and pituitary gonadotropins through an estrogen antagonist
If hypothalamic or pituitary dysfunction is detected or if oral regimens are not
successful, injectable gonadotropins are administered. The most common
gonadotropin regimens use FSH administered alone or in combination with LH,
depending on whether the patient has hypogonadotropic or eugonadotropic
Injections are initiated at low daily doses until a
dominant follicle has matured. Ovulation is then triggered with an injection of human
Gonadotropins for Ovulation Induction/Superovulation
Ingredient Product Name Strength/Dosage Form
hMG (menotropins) Menopur Powder for reconstitution: 75 IU FSH
activity and 75 IU LH activity/vial
Bravelle Powder for reconstitution: 75 IU FSH
Gonal-f multi-dose Powder for reconstitution: 450 or
Gonal-f RFF 75 IU Powder for reconstitution: 75 IU FSH
Solution: 300, 450, or 900 IU FSH/pen SC
Follistim AQ Vial Solution: 75 IU FSH/0.5-mL vial IM or SC
Powder for reconstitution: 10,000 IU
Pregnyl Powder for reconstitution: 10,000 IU
Novarel Powder for reconstitution: 10,000 IU
Ovidrel Prefilled syringe: 250-mcg r-hCG/0.5
Source: Facts & Comparisons eAnswers.
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5548530;
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/1081/5546104;
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5548528;
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5548529;
https://fco.factsandcomparisons.com/lco/action/search?q=pregnyl&t=name;
https://fco.factsandcomparisons.com/lco/action/search?q=ovidrel&t=name. Accessed June 14, 2017.
The oral and injectable medications used for OI are also incorporated into
regimens for SO. They are administered in doses and schedules intended to develop
multiple ovarian follicles, rather than one dominant follicle. This results in a greater
number of oocytes available for fertilization. Because T.R. has ovulatory cycles, but
has unexplained infertility, SO is the treatment approach considered most
CASE 48-1, QUESTION 8: What medication regimen is recommended for T.R.’s unexplained infertility?
There are multiple methods for ovulation stimulation that utilize oral or injectable
medications. Clomiphene citrate is the most common initial choice because of the
convenience and low cost of an oral regimen and the widespread experience with its
The competitive binding of CC to estrogen receptors in the hypothalamus stimulates
release of GnRH. This promotes gonadotropin release from the anterior pituitary,
leading to follicular development, increased estradiol production, and ovulation. As
previously described, the mechanism of action of CC requires an intact
hypothalamic–pituitary–ovarian axis.
25 The typical initial dosing regimen for CC is
50 mg once daily for 5 days starting between days 2 through 5 of the menstrual cycle.
Ovulation usually occurs 5 to 12 days after the fifth dose is taken. If ovulation is
documented but pregnancy does not occur, the same dose of CC is used in future
cycles. If ovulation does not occur, then the dose is increased by 50 mg with each
subsequent cycle. Although the product labeling does not recommend doses above
100 mg/day, CC doses as high as 250 mg have been described in the literature.
Superovulation for unexplained infertility with CC is recommended in combination
with intrauterine insemination (IUI), because this improves pregnancy and live birth
rates over CC alone or no intervention.
Intrauterine insemination introduces a
processed semen sample directly to the uterus via a catheter placed through the
cervix. The procedure is timed with ovulation to maximize sperm exposure for
fertilization. This is accomplished by using a urinary ovulation home test kit to
identify the natural LH surge or injecting hCG to trigger ovulation and planning the
IUI 24 to 36 hours later. Due to the nature of the procedure, patients with bilateral
obstruction of the fallopian tubes are not candidates for IUI.
T.R.’s evaluation shows no evidence of hypothalamic or pituitary dysfunction, so
she is an appropriate candidate for CC. Once her next cycle begins, she should
initiate a 5-day regimen of CC 50 mg once daily starting on the fifth day of menstrual
bleeding, with plans for an IUI following documentation of ovulation.
CASE 48-1, QUESTION 9: T.R. begins a regimen of CC and experiences hot flashes and nausea, but
chooses to complete the 5-day course. What is the likely cause of her symptoms?
Vasomotor symptoms are a common complaint during a short treatment course of
CC, occurring in approximately 10% of users. Additional side effects include
headache, breast tenderness, irritability, mood swings, and nausea. Although visual
disturbances are reported in less than 2% of patients, symptoms such as blurred
vision or light sensitivity should be reported and evaluated to prevent serious
19,25 All medications for SO can result in multiple gestation
pregnancies. Clomiphene citrate for unexplained infertility is associated with
multiple gestation in approximately 3% to 7% of pregnancies, primarily resulting in
25 Early concerns about increased rates of ovarian cancer in women exposed to
more than 12 cycles of CC have been minimized based on recent data.
In this case, T.R. is experiencing side effects commonly associated with CC. They
are not treatment limiting, and she is not reporting a change in vision that would
require further evaluation. She can safely proceed with treatment by monitoring for
an LH surge using a home ovulation test kit and undergoing IUI.
options are available for this couple?
Multiple treatment cycles with the combination of CC and IUI are commonly
pursued, but there is little evidence for effectiveness beyond six attempts.
cases, alternatives to CC for SO may be desirable because of poor tolerability or
treatment failure. Aromatase inhibitors or gonadotropins are suitable alternatives to
The aromatase inhibitors letrozole and anastrozole are oral alternatives to CC,
although they are not FDA-labeled for OI or SO. Aromatase is an enzyme that
converts androstenedione to estrone and testosterone to estradiol. Aromatase
inhibitors reduce systemic estrogen levels by blocking this conversion in the ovary,
resulting in increased gonadotropin secretion and follicular development. The higher
concentration of androgens that remains in the ovary increases follicular sensitivity to
FSH and further facilitates development.
The recommended administration schedule is similar to clomiphene: once daily for
5 days beginning on cycle days 3 to 5. Although daily doses of letrozole 2.5 or 5 mg
or anastrozole 1 mg have been studied for this purpose, there is more evidence
available for letrozole. Pregnancy rates with letrozole appear to be similar to that of
28 Adverse effects experienced with aromatase inhibitors resemble those of CC
and include vasomotor symptoms, nausea, and fatigue. The aromatase inhibitors do
not affect cervical mucus or endometrial development, but this finding has not
translated into improved pregnancy outcomes in clinical studies. Development of
fewer follicles may result in a lower risk of multiple gestation pregnancy compared
with CC. Initial concerns of the teratogenic potential of aromatase inhibition during
fetal development prompted a warning against use in premenopausal women who are
27 However, surveillance studies do not demonstrate higher
rates of congenital malformations with letrozole as compared to CC.
timing of administration in the cycle reduces the risk of fetal exposure. Continued
monitoring of pregnancy outcomes is needed to confirm safety.
If oral agents are unsuccessful, SO can be attempted with injectable gonadotropins
including FSH alone or in combination with LH (Table 48-3).
involves daily injections of FSH or a combination of FSH and LH to stimulate
follicular development. Human chorionic gonadotropin is commonly administered as
a single injection to finalize follicular development and induce ovulation.
recommendations, key differences between formulations, and risks associated with
gonadotropin use are reviewed in more detail in Case 48-2.
T.R.’s complaints of vasomotor symptoms are well documented with CC.
Although the aromatase inhibitors are another oral option, the likelihood of hot
flashes is similar. However, if the couple continues to be unsuccessful with future
cycles of CC plus IUI, letrozole can serve as an alternative prior to use of injectable
gonadotropins. In vitro fertilization (IVF) is commonly reserved until after multiple
IUI procedures are attempted and unsuccessful.
Description of Select Infertility Procedures
Classification Procedure Description
Insemination Intrauterine, intracervical, intravaginal Delivery of a prepared semen sample to the
intended site (vagina, cervix, uterus) during
Assisted hatching Mechanical or chemicalseparation of the
blastocyst from the zona pellucida (membrane
surrounding the oocyte) during embryonic
Embryo cryopreservation Freezing and storage of embryos for future ART
Gamete intrafallopian transfer Laparoscopic transfer of the unfertilized oocytes
and sperm to the fallopian tube for fertilization
In vitro fertilization—embryo transfer Transfer of one or more embryos resulting from
in vitro fertilization into the uterus through the
Intracytoplasmic sperm injection In vitro injection of the sperm into the oocyte
Examination of oocytes, zygotes, or embryos for
specific genetic conditions (diagnosis) or for
general genetic alterations (screening)
Zygote intrafallopian transfer Laparoscopic transfer of the fertilized oocyte
(zygote) into the fallopian tube
ART, assisted reproductive technology.
Assisted Reproductive Technology
There are a variety of procedures to address infertility factors specific to each
couple. Insemination processes (intrauterine, intracervical, and intravaginal) are
categorized separately from those using assisted reproductive technology (ART), or
the manipulation of oocytes and embryos (Table 48-4).
Control and Prevention monitors ART in the United States through the National ART
Surveillance System. The use of ART is trending upward, with the number of cycles
increasing from just over 122,000 in 2003 to more than 157,000 in 2012.
The primary ART is IVF, which involves retrieval of oocytes after SO,
fertilization in vitro, and transfer of the embryo(s) directly to the uterus through the
cervix, bypassing the fallopian tubes (Fig. 48-2; Table 48-4).
sperm injection (ICSI), or the injection of sperm directly into the oocyte during the
fertilization process, accompanies IVF if severe sperm dysfunction is evident. A
variety of ancillary procedures can be used based upon each couple’s history and
clinical presentation. These include genetic screening and cryopreservation of
embryos. Assisted reproductive technology also allows couples to use donor sperm
and/or oocytes to overcome severe sperm or ovarian dysfunction that cannot be
addressed through other methods. The option of using donor oocytes uniquely targets
infertility due to diminished ovarian reserve.
Figure 48-2 In vitro fertilization process.
QUESTION 1: F.J., a 39-year-old woman, and her 42-year-old husband are a recently married couple
What findings support female factor infertility?
This couple is undergoing evaluation of infertility after only 6 months without
conceiving because of F.J.’s advanced age (older than 35) and history of chlamydia,
which places her at increased risk of complications from pelvic inflammatory
disease. The occlusion of her fallopian tubes is most likely from the chlamydial
infection at age 21, which may or may not have been detected and treated at that time.
Laparoscopy would be necessary to rule out any additional causes such as
endometriosis. Further hysteroscopic procedures are warranted to define the location
and type of obstruction and to determine whether surgical repair is feasible.
regular menstrual cycle length and history of dysmenorrhea is supportive of an
ovulatory menstrual cycle and her CC challenge test shows adequate ovarian reserve,
with normal levels of FSH and estradiol. She is within the normal weight range and
has normal findings upon physical examination. However, further laboratory testing
may be warranted to confirm normal thyroid and pituitary function and rule out
findings associated with PCOS.
CASE 48-2, QUESTION 2: F.J.’s husband has normal findings upon physical examination. His semen
analysis yields the following results:
Sperm progressive motility, 30%
A repeat analysis produces similar results. Additional laboratory findings include:
The semen analysis is significant for sperm motility and morphology values below
the lower reference limit defined by the World Health Organization. The semen
volume, sperm number, and vitality measurements are just above the lower reference
Interventions to improve sperm parameters typically target the
underlying cause if possible, such as treatment of hyperprolactinemia or
supplementation with testosterone. In some cases, sperm production can be
stimulated through the use of medications that influence the hypothalamic–pituitary–
testicular axis. For example, CC may improve sperm concentrations in men with
hypogonadotropic hypogonadism by stimulating hypothalamic release of GnRH.
There is no consensus regarding the optimal dosage regimen, which is FDA-labeled
for use in women only. Small clinical studies have examined CC in initial daily
doses of 12.5 to 25 mg, in addition to alternate-day and cyclic dosing for treatment
periods of several months with positive results.
33 Administration of various regimens
of injectable gonadotropins (FSH, LH, or hCG) also improves pregnancy rates.
Given this patient’s normal serum testosterone and FSH, CC or gonadotropins are not
recommended therapies. His prolactin is normal as well, ruling out this potential
secondary cause. In this case, there is no identifiable cause of the abnormal
parameters so it is deemed idiopathic, without a known etiology.
Some small studies have demonstrated improvement in sperm motility, concentration,
and morphology. A systematic review documented a possible increase in live birth
rates with the use of antioxidants.
34 F.J.’s husband may choose to take a daily
antioxidant supplement as they move forward with other treatment modalities.
Insemination procedures are one approach to address abnormal findings on semen
analysis. Bypassing the cervix and placing the sperm closer to the fallopian tubes
near the time of ovulation can overcome lower sperm counts and motility issues. In
regard to this couple, however, F.J. does not have patent fallopian tubes and would
not be a candidate for IUI. An ART procedure will be necessary to address both
female and male infertility factors.
IVF is more appropriate than gamete intrafallopian transfer and zygote
intrafallopian transfer due to F.J.’s tubal findings. Although surgical repair of the
obstructed fallopian tubes may be possible in some cases, many couples choose to
bypass this option and pursue ART, especially when there are additional male
32 F.J. will need a surgical evaluation to confirm whether this is
recommended prior to proceeding to ART. F.J. is ovulatory with adequate ovarian
reserve, so the use of donor oocytes is not required. Her husband’s abnormal sperm
parameters can be addressed through ICSI, with the option of using donor sperm in
The basic steps in an IVF protocol include SO/COS, oocyte retrieval, fertilization,
embryo culture, and embryo transfer. Medications are primarily used during three
main stages of IVF: COS, oocyte retrieval, and luteal phase support (Table 48-5).
(For a step-by-step guide to all the steps in this complex process, go to
vary widely in the medications used, dosing regimens, and timing of administration.
A sample in vitro fertilization protocol representing F.J.’s experience is provided in
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