CASE 48-2, QUESTION 3: After the completed evaluation, the couple chooses to undergo IVF with
recommended to initiate the IVF protocol?
Stage One: Controlled Ovarian Stimulation/Superovulation
The purpose of COS for IVF is the development of multiple follicles for oocyte
retrieval. Although oocyte retrieval and fertilization can be performed during a
normal ovulatory cycle without stimulation, it is more common and many times
necessary to use this process.
Controlled ovarian stimulation for IVF is designed to manipulate follicular
development for oocyte retrieval at the most optimal stage of maturation. Many
protocols start with the administration of oral contraceptives for up to 28 days in the
preceding menstrual cycle. This serves to control the timing of the onset of the next
menses in order to plan for initiating the COS regimen.
35 This is particularly pertinent
in women who have irregular or long menstrual cycles, but is also common practice
in those with regular menstrual cycles. F.J. has a history of regular menstrual cycles,
but is still a candidate for oral contraceptive therapy to conveniently time the
remainder of the treatment course.
Role of Medications in an In Vitro Fertilization Cycle
Oral contraceptives Control the onset of menses and the start of controlled
Prevent a premature LH surge or disruption of
controlled ovarian stimulation
Stimulate development of multiple ovarian follicles for
Stage two: oocyte retrieval hCG Induce final follicular maturation to prepare for oocyte
Progesterone Maintain the endometrium for embryo transfer and
Gonadotropin-Releasing Hormone Analogs
Once the COS process begins, it can be interrupted by an endogenous surge of LH
that triggers ovulation prematurely and threatens the success of the cycle. Most
protocols use medications to limit the influence of any endogenous hormone levels as
the cycle progresses. Gonadotropin-releasing hormone agonists have been used for
this purpose for several decades. Administration of a GnRH agonist initially
increases pituitary gonadotropin release, often referred to as a “flare.” Continued
daily administration leads to receptor downregulation and reduced pituitary secretion
of LH and FSH, allowing for direct administration of the gonadotropins by
The most common IVF regimens in the United States use either subcutaneous
leuprolide or intranasal nafarelin (Table 48-6).
23 The leuprolide formulation is often
dosed in “units” using an insulin syringe to permit measurement of small volumes.
Daily doses of 10 to 20 “units” correspond with 0.5 to 1 mg using the 1 mg/0.2 mL
product. The depot formulations of leuprolide or goserelin acetate used for
endometriosis or hormone-dependent cancers may require higher doses and longer
duration of gonadotropin administration for COS.
studied in doses of 200 to 400 mcg twice daily.
variable depending on the administration technique, dosage interval, sneezing, or use
39 However, studies indicate that pregnancy rates between the
Figure 48-3 Sample in vitro fertilization protocol (Case 48-2).
Gonadotropin-Releasing Hormone Analogs for In Vitro Fertilization
Analog Product Name Strength/Dosage Form
GnRH agonist Nafarelin acetate
Leuprolide acetate 1-mg/0.2-mL kit SC
GnRH antagonist Cetrorelix acetate
aFDA-labeled for use with assisted reproductive technology procedures.
Source: Facts & Comparisons eAnswers.
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5548533;
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5550316;
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5548535;
https://fco.factsandcomparisons.com/lco/action/doc/retrieve/docid/fc_dfc/5548534; Accessed June 14,
2017. GnRH, gonadotropin-releasing hormone; IM, Intramuscular; SC, subcutaneous.
Treatment protocols are identified by the timing of GnRH agonist administration.
In a traditional “long” protocol, a GnRH agonist is initiated during the follicular or
luteal phase of the preceding menstrual cycle. Once gonadotropins are initiated, the
GnRH agonist is continued at half the daily dose until ovulation is stimulated. If an
oral contraceptive is used for pretreatment, the GnRH agonist is often initiated within
the last week of the contraceptive regimen. In a “short” protocol, a GnRH agonist is
administered in conjunction with the gonadotropins for the stimulation cycle. When
used in this manner, the flare, or initial increase in gonadotropin production, aids in
the initial recruitment and development of follicles. The continued administration at a
lower dose serves to suppress the LH surge. An “ultrashort” protocol reserves the
use of the GnRH agonist for just the first 3 days of gonadotropins. The fewer
injections in the shorter protocols potentially improves cost and patient convenience.
Many other variations of the long and short protocols that adjust the length of GnRH
agonist use, dose, and timing of discontinuation are utilized, with wide variability
Alternatively, the immediate suppression of gonadotropin secretion using GnRH
antagonists such as cetrorelix and ganirelix allows for a shorter duration of
administration and improved convenience (Table 48-6).
FSH and LH flares reduces the incidence of ovarian cysts that can occur with the
injection or a lower-dose daily injection that is continued until ovulation is
36,40 Ganirelix is administered as a daily 250-mcg subcutaneous injection
and cetrorelix is either a daily subcutaneous injection of 0.25-mg or a single 3-mg
23 The timing of initiation is either “fixed” on a particular day of stimulation or
“flexible” based on follicular development.
40 Available data suggest that there is no
difference in pregnancy and live birth rates between GnRH agonist and antagonist
In this case, a protocol using a GnRH agonist is chosen for F.J. For the preparation
phase, an injectable (such as leuprolide) or intranasal (nafarelin) product can be
used. The administration of GnRH analogs in the long protocol is associated with hot
flashes, headaches, and sleep disturbances due to hypoestrogenic effects. Concurrent
administration of oral contraceptives may help lessen these responses.
intranasal product may appear preferable given F.J.’s concerns about injections.
Local reactions at the injection site and nasal and throat irritation are adverse effects
expected with the subcutaneous and intranasal routes of administration,
39,42 However, the symptoms and duration of her seasonal allergic
rhinitis should be clarified because the absorption of the intranasal product can be
affected by sneezing, congestion, and use of other intranasal medications. Thorough
discussion and demonstration of the subcutaneous injection technique can also reduce
a patient’s fears regarding this route of administration. After discussion, F.J. agrees
to administer leuprolide injections. Once she experiences her next menses, she will
begin 21 days of an oral contraceptive. On day 16 of this regimen, she will initiate
leuprolide 1 mg once daily as a subcutaneous injection in conjunction with the oral
contraceptives. A calendar will be provided to help her track the daily doses.
What is the recommended gonadotropin regimen for F.J.?
The exogenous administration of FSH alone or in combination with LH is intended
to mimic the natural process of follicular recruitment and maturation. Gonadotropins
are available from urinary and recombinant methods (Table 48-3).
menopausal gonadotropin (hMG) was the first gonadotropin used in the United States
as early as the 1950s. The product is extracted from urine of postmenopausal women
and standardized to contain 75 IU each of FSH and LH activity. Both LH and hCG
are present in the preparation and contribute to the LH activity. Urofollitropin is a
urinary FSH that when first marketed in the 1980s retained small amounts of LH and
other urinary proteins that were not clinically active. A highly purified urofollitropin
is now available that can be injected subcutaneously in place of the earlier
intramuscular preparations. The development of the recombinant FSH products
(follitropin alfa and follitropin beta) further expanded treatment options in the late
1990s. Although they have unique chemical structures, they result in clinically similar
Women with hypogonadotropic hypogonadism require administration of both FSH
and LH because their low endogenous LH levels do not support follicular
development. This is achieved through the administration of hMG. Women with
normal pituitary function can receive injections of FSH alone, either as urofollitropin
or a recombinant product. It is generally demonstrated that urinary hMG and
recombinant FSH result in similar pregnancy rates, and there is no consensus
recommendation for one preparation over the other.
Dosage regimens for the gonadotropins are intended to promote multiple follicles
the status of the developing follicles. Treatment may continue for 7 to 12 days,
although longer courses may be necessary depending on follicular response. If
subsequent cycles are needed, the initial treatment doses are chosen based on the
stimulation achieved in the first cycle.
F.J. is undergoing her first cycle of IVF, so there are no data regarding prior
gonadotropin response to guide the dose selection. She has no signs of hypothalamic
or pituitary dysfunction so she can receive FSH alone or in combination with LH. All
of the available highly purified or recombinant products require daily subcutaneous
injections. Although this may be a concern for F.J., this is an advantage over earlier
formulations that required intramuscular injection. All products require reconstitution
of one or more vials of lyophilized powder just prior to injection except certain
formulations of the recombinant follitropin alfa and beta. The two recombinant FSH
formulations are available in pen injection devices that avoid the need for
reconstitution and reduce the complexity of the dose preparation and injection
23 Patient education should focus on product-specific
instructions for storage, preparation for injection, and the correct subcutaneous
injection technique. All products have patient-friendly video demonstrations or
handouts available on the Internet to facilitate this process. (For helpful training
videos and patient handouts that describe the dose preparation and injection
technique, see https://www.ferringfertility.com/products/, and
https://fertilitylifelines.com/fertility-treatments/injection-instructional-videos/.)
The patient should be instructed to anticipate possible injection-site reactions as well
as psychological symptoms of irritability, mood swings, and depression which may
After consideration of these issues, a recombinant FSH product is chosen for F.J.
because of the convenience of the pen device. She will begin a dose of 225 IU of
recombinant follitropin alfa injected subcutaneously once daily.
leuprolide injections. What medication monitoring should be provided at this time?
The goal of gonadotropin therapy is to guide the development of multiple follicles
for oocyte retrieval without increasing the risk for ovarian hyperstimulation
syndrome (OHSS), a rare but serious complication of COS. In its most severe form,
this syndrome is characterized by increased systemic vascular permeability that can
result in ovarian rupture, thromboembolism, renal failure, and adult respiratory
distress syndrome. The risk for this condition correlates most directly with the
development of multiple ovarian follicles. Additional risk factors include younger
age, low body weight, and history of PCOS. Routine monitoring of ovarian follicular
development allows the clinician to maximize efficacy and reduce the risk for
Typical monitoring includes vaginal ultrasounds and serum estradiol
measurements performed every 1 to 3 days during the COS phase. The monitoring
frequency increases as the follicular development advances, and the gonadotropin
doses may be reduced or increased depending on the number and size of the follicles.
If hyperresponse is evident, the cycle may be cancelled prior to oocyte retrieval.
An alternative to cycle cancellation is “coasting,” or discontinuation of
gonadotropins until serial estradiol measurements show a plateau or declining
Once F.J. initiates therapy, she is scheduled for serum estradiol and vaginal
ultrasound measurements every other day. This increases to daily monitoring on day
7 of the combination of leuprolide and follitropin alfa because the number and size of
the follicles continue to increase.
ready for oocyte retrieval. What medication regimen is recommended at this time?
Chorionic gonadotropin is administered in preparation for oocyte retrieval to
simulate the effect of the physiologic LH surge on final oocyte maturation. The oocyte
retrieval must be carefully timed to coincide with the completion of the oocyte
maturation process, just prior to ovulation. Many clinics schedule oocyte retrieval
between 34 and 36 hours after chorionic gonadotropin is injected.
Chorionic gonadotropin is available from urinary or recombinant sources. The
urinary hCG product is administered as a single intramuscular injection of 5,000 to
23 Doses of 5,000 IU may be administered to patients who are deemed to
45 The dose of the recombinant product is 250 mcg injected
23 A single dose of a GnRH agonist is an alternate method of
triggering LH release in IVF protocols that incorporate a GnRH antagonist. This
approach appears to reduce the risk for OHSS, but may lower pregnancy rates.
received the GnRH agonist leuprolide in her prestimulation period so she would not
be eligible for this approach.
Given F.J.’s concerns regarding injections and the fact that she has been
administering the follitropin alfa subcutaneously, it is prudent to continue with this
route of administration. F.J. is instructed to inject a single 250-mcg dose of
recombinant chorionic gonadotropin subcutaneously. She will discontinue leuprolide
and follitropin alfa at this time.
Ovarian Hyperstimulation Syndrome
CASE 48-2, QUESTION 7: F.J. undergoes a transvaginal oocyte retrieval procedure 36 hours after the
additional counseling is recommended for F.J. after the oocyte retrieval?
As previously described, OHSS is a rare complication associated with COS.
Careful monitoring of estradiol levels and follicular development on ultrasound
limits the incidence. However, if symptoms develop, it is typically within 1 to 2
weeks after oocyte retrieval. It is generally categorized as mild, moderate, or severe,
and can occur early (within 9 days after oocyte retrieval) or late (after 10 days, often
45,47 The clinical signs of OHSS are thought to result
from increased capillary permeability due to high levels of vascular endothelial
growth factor. However, the specific underlying pathology is poorly understood. A
mild presentation of OHSS consists primarily of gastrointestinal symptoms
(abdominal pain, nausea, diarrhea, bloating) or weight gain, especially abdominal
distension. A patient experiencing these symptoms will be instructed to avoid
physical activity, maintain oral fluid intake of at least 1 L/day, and monitor daily
weights and urine output. The patient should report any weight gain of 2 lb or more to
allow for more intensive outpatient monitoring of liver and renal function,
electrolytes, and hematologic parameters. If the condition progresses, the patient may
require hospitalization for monitoring and treatment of severe outcomes such as
thromboembolism, renal failure, pulmonary distress, or ovarian rupture.
There were no initial indications of hyperstimulation during F.J.’s COS regimen,
so she will be instructed to monitor for signs of OHSS during the 2 weeks after
oocyte retrieval. She should notify her physician if she experiences gastrointestinal
symptoms or weight gain, even if the symptoms are mild. This will facilitate early
monitoring to maximize safety during the remainder of the IVF process.
Stage Three: Luteal Phase Support
Which agent should be selected?
Supplemental progesterone is administered immediately after oocyte retrieval to
provide additional “luteal phase support” during IVF. The luteal phase of the
menstrual cycle (Fig. 48-1) is dominated by progesterone released by the corpus
luteum that prepares the endometrium for implantation of the fertilized ovum. The
disruption of follicles during the oocyte retrieval process delays production of
progesterone, necessitating supplementation. Additionally, cycles that utilize a GnRH
agonist may be complicated by residual inhibition of pituitary LH secretion and
progesterone production into the luteal phase.
Progesterone is available in oral, vaginal, or injectable formulations (Table 48-
Intramuscular injection of progesterone in oil in a daily dose of 50 mg was the
first method used for supplementation and continues to be widely used. However,
alternatives to progesterone in oil have been sought due to frequent reports of rash
and discomfort at the injection site.
Vaginal progesterone preparations have gained popularity for luteal phase support
due to ease of administration and avoidance of injection-site reactions. The 8%
progesterone vaginal gel and the 100 mg vaginal insert are the only commercially
available FDA-labeled preparations for use in ART procedures. The gel is
administered as one 90-mg applicator once or twice daily. The dose of the vaginal
insert is 100 mg either twice a day (every 12 hours) or 3 times a day (every 8
48–50 Patient education should focus on the correct technique for intravaginal
administration. Both products utilize a disposable applicator to facilitate correct
placement. (Detailed patient instructions are provided by both manufacturers.
https://www.ferringfertility.com/products/endometrin/ and
https://www.allergan.com/assets/pdf/crinone_pi.) The vaginal preparations may
cause local irritation and vaginal discharge, although the vaginal gel is generally
associated with less discharge than the inserts or suppositories. Clinical studies
suggest no difference in pregnancy rates between vaginal and intramuscular
formulations, so clinician and patient preferences often dictate the selection.
Commercially Available Progesterone Products Used in Assisted Reproductive
Product Name Strength/Dosage Form Route of Administration
Endometrin 100-mg vaginal insert
FIRST-Progesterone VGS 50-, 100-, 200-, 400-mg vaginal
Progesterone 50 mg/mL (oil) Intramuscular
aFDA-labeled for luteal phase support.
Source: Facts & Comparisons eAnswers. https://fco.factsandcomparisons.com/lco/action/search?
q=crinone&t=name; Accessed June 14, 2017.
Oral formulations are not recommended for the purpose of luteal phase support
with ART due to lower absorption and reduced pregnancy rates.
formulations are widely available, including oral micronized progesterone and
progesterone vaginal suppositories, gels, and creams. In some cases, patients are
instructed to insert oral progesterone formulations intravaginally.
Progesterone is initiated after oocyte retrieval until a pregnancy test is performed
and then continued until at least 8- to 10-week gestation.
48 Data suggest that there are
no significant risks to the mother or fetus from supplemental progesterone during this
Comments
Post a Comment
اكتب تعليق حول الموضوع