Sweet spot

ORIGINAL ARTICLE: ASSISTED REPRODUCTION
Defining the ‘‘sweet spot’’ for
administered luteinizing
hormone-to-follicle-stimulating
hormone gonadotropin ratios during
ovarian stimulation to protect against
a clinically significant late follicular
increase in progesterone: an analysis
of 10,280 first in vitro
fertilization cycles*
Marie D. Werner, M.D.,a Eric J. Forman, M.D.,a,b Kathleen H. Hong, M.D.,a Jason M. Franasiak, M.D.,a
Thomas A. Molinaro, M.D., M.S.C.E.,a,b and Richard T. Scott Jr., M.D., H.C.L.D.a,b
a Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Robert Wood
Johnson Medical School, Rutgers University, New Brunswick; and b Reproductive Medicine Associates of New Jersey,
Basking Ridge, New Jersey
Objective: To determine whether different ratios of administered LH-to-FSH influence the risk of clinically relevant late follicular
P elevations and whether there is an optimal range of LH-to-FSH to mitigate this risk.
Design: Retrospective cohort.
Setting: Private academic center.
Patient(s): A total of 10,280 patients undergoing their first IVF cycle.
Intervention(s): None.
Main Outcome Measure(s): The ratio of exogenous LH-to-FSH throughout stimulation and association with absolute serum P level
R1.5 ng/mL on the day of hCG administration.
Result(s): Stimulations using no administered LH (N ¼ 718) had the highest risk of P elevation R1.5 ng/mL (relative risk [RR] ¼ 2.0;
95% confidence interval [CI] 1.8–2.2). The lowest risk of P increase occurred with an LH-to-FSH ratio of 0.30:0.60 (20%; N ¼ 4,732). In
contrast, ratios <0.30, reflecting proportionally less administered LH (N ¼ 4,847) were at increased risk for premature P elevation (32%,
RR¼1.6; 95% CI 1.5–1.7) as were ratios>0.60 (23%, RR 1.1; 95% CI 1.0–1.3). This pattern of lowest risk in the 0.30–0.60 range held true
for cycles characterized by low, normal, and high response. When performing a logistic regression to control for multiple confounding
variables this relationship persisted.
Received April 3, 2014; revised July 3, 2014; accepted July 7, 2014.
*This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
M.D.W. has nothing to disclose. E.J.F. has nothing to disclose. K.H.H. has nothing to disclose. J.M.F. has nothing to disclose. T.A.M. has nothing to disclose.
R.T.S. has nothing to disclose.
Reprint requests: Marie D. Werner, M.D., Reproductive Medicine Associates of New Jersey, 140 Allen Road, Basking Ridge, New Jersey 07920 (E-mail:
mwerner@rmanj.com).
Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00
Copyright ©2014 The Authors. Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.fertnstert.2014.07.766
VOL. - NO. - / - 2014 1

Conclusion(s): Absent or inadequate LH dosing is associated with a risk for a late follicular elevation in P sufficient to induce suboptimal
outcomes. A total LH-to-FSH ratio of 0.30:0.60 was associated with the lowest risk of P
elevation. Optimization of this parameter should be considered when making gonadotropin
dosing decisions. (Fertil Steril 2014;-:-–-. 2014 by American Society for Reproductive
Medicine.)
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The hormonal milieu, which accompanies a supraphy-siologic
response to controlled ovarian hyperstimula-tion
(COH), has been associated with impaired
endometrial receptivity. Much of this diminution has been
attributed to significant increases in circulating E2 concentra-tions;
however, other changes that accompany superovula-tion
may also impact endometrial receptivity. One such
factor may be subtle increases in P levels during the late
follicular phase (1, 2). These P elevations are important as
they prognosticate suboptimal clinical outcomes (3–5).
Early literature describing these elevations assumed that
they were part of the spectrum of early and excessive LH
effect on the maturing follicles. As such, they were termed pre-mature
luteinization (6, 7). There are twopotential sources of LH,
either exogenous from injectable gonadotropins or endogenous
from the pituitary. Given the near universal practice of
administering a GnRH agonist or a GnRH antagonist during
stimulation, premature LH surges should be uncommon and
pointed to exogenous LH as a possible causative agent.
More recently, studies have compared the prevalence of pre-mature
P elevations in patients receiving pure FSH stimulations
to those receiving hMG alone (8, 9). Given that the hMG group
received pharmacologic levels of LH stimulation, it might
seem intuitive that they would have had a higher prevalence
of premature P elevations. In fact, those women receiving
hMG had a lower risk. This suggests that a relationship
between LH and premature P elevations is complex and may
not be wholly attributed to excessive stimulation.
These data suggest that optimizing the effect of LH during
COH may be dependent on both the level of exogenous LH and
FSH that are administered (10–12). The impact of different
administered LH-to-FSH ratios during stimulation have not
been studied in detail. To that end, this study seeks to deter-mine
whether different ratios of LH:FSH activity in stimula-tion
protocols impact the risk for premature P elevation and
whether those differences also apply to different ovarian
response groups.
MATERIALS AND METHODS
Population
In this retrospective cohort study, all patients attempting
conception through IVF from October 1999 to May 2013 were
reviewed. Patients undergoing their first IVF cycle in this pro-gram
and whose superovulation protocol used either GnRH
agonist down-regulation or a GnRH antagonist were selected
for further study. Patients using microdose GnRH agonist flare
protocols were excluded, as there was no mechanism to quan-tify
the contribution of endogenous LH release on the overall
level of LH stimulation. Patient characteristics and demo-graphic
information were recorded. Response to stimulation
was measured by the number of mature metaphase II oocytes
obtained after vaginal oocyte retrieval. This retrospective anal-ysis
of data was Institutional Review Board approved by West-ern
Institutional Review Board, protocol 20021333.
Study Design
The purpose of this study was to determine whether variations
in the relative amounts of exogenous LH and FSH impact the
risk for significant P elevations before the administration of
hCG to induce final oocyte maturation. The ratio of exoge-nous
LH to FSH was calculated based on the total dose of
each medication administered throughout the cycle. Starting
dosages and protocol were selected by the primary physician
in relation to patient characteristics, such as age, ovarian
reserve, and prior history, but were also guided by insurance
restrictions. Overall medication dosages maintained a rela-tively
constant ratio throughout the stimulation as per prac-tice
standards. Although doses infrequently changed
throughout the cycle, this metric was believed to be the
most reflective of total LH exposure. Serum levels of LH and
FSH were not routinely measured during cycles.
The quantity of FSH was expressed in international units
and was based on total FSH dose without regard to whether it
was from a pure FSH preparation (recombinant or purified),
an hMG preparation, or a combination of the two. The quan-tity
of LH was also expressed in international units when us-ing
hMG or recombinant LH. One ampule of hMG was
considered to have 75 IU of LH activity. In the case of low
dose hCG administration, 10 IU was designated to be equiva-lent
to 75 IU of LH. Starting and total doses of exogenous LH
and FSH were recorded for each included cycle. The LH-to-
FSH ratio was calculated by simply dividing the total LH
dose by the total FSH dose administered. Serum P levels
were measured throughout the cycle, and the P level on the
day of hCG administration was also documented to assess
for clinically significant late follicular P elevations.
Assay
Serum P was determined using the Immulite 2000 immuno-assay
system (Siemens). The interassay coefficient of variation
2 VOL. - NO. - / - 2014

(CV) was 5.58% and intra-assay CV was 5.25% for this system.
For the purposes of this study, P levelsR1.5 ng/mL on day of
hCG administration were characterized as a late follicular in-crease
in P, based on a review of internal data that showed the
same diminution in outcome as published literature (1, 13)
(data not shown).
Cycles were stratified based on the total ratio of exoge-nous
LH to exogenous FSH used. (For example a patint who
received a protocol with a starting dose of 150 IU of recombi-nant
FSH and 2 ampules of hMG and maintained this dose for
10 days of stimulation would have received a total exogenous
LH dose of 1,500 IU and a total exogenous FSH dose of 3,000
IU and would be categorized as having an LH-to-FSH ratio of
0.5.) A total of 18 groups of exogenous LH-to-FSH exposure
were defined to compare meaningful data points in a large
population. These 18 groups spanned a ratio from no exoge-nous
FSH (0) to ratiosR0.81, with an incremental increase of
0.05 between each group.
The data were then stratified relative to ovarian response
and the same groups were identified in relation to the number
of mature oocytes obtained. This was in an effort to control
for the intrinsic differences in response groups, as each group
was exposed to varying levels of endogenous LH, which may
impact overall outcomes. Low ovarian response was defined
as a cycle in which %4 metaphase II oocytes were retrieved.
Similarly, a normal response was defined by having 5–19
metaphase II oocytes retrieved and high response by R20
mature oocytes.
Statistical Analyses
Statistical analysis was performed using Analyse-it for Excel
version 2.26 and STATA version 12. A contingency table was
applied for categorical variables and a receiver operator char-acteristic
curve was used to determine the optimal ratio of LH-to-
FSH administered. Statistical significance was set at
P.05. This analysis was performed for the population as a
whole, and then repeated for the group analysis. Logistic
regression was used for the entire population to model the
relationship between elevated serum P (R1.5 ng/dL) and
the starting LH-to-FSH ratio as a continuous variable and
as a dichotomous variable using cutoffs of 0.3 and 0.6, as
Fertility and Sterility®
well as comparing those subjects with the range of 0.3–0.6
to all others. Confounding variables including the number
of follicles, age, stimulation protocol, serum E2 at the time
of trigger, and diagnosis were controlled for using multivar-iate
logistic regression.
This study does not include a direct comparison of im-plantation
and delivery rates in the various LH-to-FSH ratio
groups. This reflects the fact that clinical management was
not similar in the various groups. During the study interval,
transfer timing was influenced by the presence or absence
of P levels 1.5 ng/mL on the day of hCG administration.
When elevations were detected, embryos were typically cryo-preserved
and transferred in a subsequent cycle. Thus patients
in groups with higher or lower risks for P elevations would
have very different transfer strategies preventing meaningful
comparison of cycle outcomes such as pregnancy rates (PRs).
RESULTS
Population Characteristics
A total of 10,280 cycles were included for analysis. There were
5,393 cycles using a GnRH agonist down-regulation protocol
and 4,887 using an antagonist protocol. The average age of
patients included was 34.7 4.3 years. The average
maximum FSH value on day 3 was 6.42.4 IU/L. The average
body mass index (BMI) was 25.4 5.9 kg/m2. Additional de-mographic
information is provided in Table 1.
In the group analysis there were a total of 1,803 low
response cycles, with an average age of 36.5 4.2 years,
FSH 7.0 2.7 IU/L, and BMI 25.1 5.8 kg/m2. The normal
response group included 7,218 cycles with an average age
of 34.6 4.2 years, FSH 6.4 2.3 IU/L, BMI 25.5 5.9 kg/
m2. In the high response group, there were a total of 1,259
cycles with an average age of 33.1 4.0 years, FSH 5.6
1.9 IU/L, BMI 25.3 5.8 kg/m2.
Evaluation of the Ratio of Total Exogenous LH-to-
FSH Dosing in Stimulation
Cycles were stratified based on the ratio of LH-to-FSH into the
18 designated small groups. A receiver operator characteristic
curve was then created and two critical breakpoints were
TABLE 1
Demographic information.
Primary diagnosis
category
No. of
patients (%)
Age (y)
(mean ± SD)
Day 3 FSH (IU/L)
(mean ± SD)
BMI (kg/m2)
(mean ± SD)
No. of antral
follicles
(mean ± SD)
Estradiol on day
of surge (pg/mL)
No. of M2s
(mean ± SD)
DOR 436 (4) 38.5 3.8 7.6 3.0 24.3 4.6 8.3 4.4 1,365.9 718.9 6.2 4.4
Endometriosis 666 (6) 33.7 3.9 6.5 2.3 24.1 4.6 11.5 7.1 1,843.0 1,004.1 9.0 6.7
Male 3,422 (33) 33.9 4.2 6.5 2.3 25.3 5.6 13.6 7.4 2,046.9 1,121.7 11.2 6.8
Other 894 (9) 35.0 4.3 6.5 2.4 25.0 5.3 12.5 7.5 1,954.8 1,096.5 10.8 7.2
Ovulatory dysfunction 2,327 (23) 33.4 4.3 5.8 2.3 26.7 7.2 17.6 10.9 2,254.5 1,217.5 12.7 8.1
Tubal 1,118 (11) 34.6 4.0 6.7 2.3 25.9 5.7 12.0 7.1 1,995.7 1,117.0 10.5 7.5
Unknown 1,200 (12) 34.7 4.2 6.5 2.2 24.0 4.7 12.7 8.0 2,042.6 1,047.6 9.9 6.7
Uterine 217 (2) 36.2 4.1 6.6 2.2 25.8 6.0 11.6 6.6 1,964.9 1,020.5 9.8 6.9
Note: BMI ¼ body mass index; DOR ¼ diminished ovarian reserve; M2 ¼ metaphase II oocyte.
Werner. Gonadotropin ratios alter risk of P increase. Fertil Steril 2014.
VOL. - NO. - / - 2014 3

identified at which the LH-to-FSH ratio was associated with
the greatest risk in a premature increase in P, specifically
0.30 or 0.60. Once these breakpoints were determined,
groups of exposure were compared to ascertain the optimal
range of exogenous LH to exogenous FSH associated with
the lowest risk of a premature increase in P. The lowest risk
of a premature increase in P was noted in the seven groups
spanning the LH-to-FSH ratio of 0.30–0.60 (20%; N ¼
4,732; P.001).
Population Outcomes
Controlled ovarian stimulations using a ratio of 0.30 to 0.60
had the lowest risk of a premature increase in P with only
20% of cycles exhibiting this pattern. This group was then
compared with cycles using no LH, a lower proportion of
exogenous LH, or a higher proportion of exogenous LH. Pa-tients
using no LH in their stimulation had a 40% chance of
exhibiting a premature increase in P and this was statistically
higher than the aforementioned group (P.001, relative risk
[RR] ¼ 2.0; 95% confidence interval [CI] 1.8–2.2). Similarly,
32% cycles with an LH-to-FSH ratio of 0.30 had a prema-ture
increase in P (P.001; RR¼1.6, 95% CI 1.5–1.7). Finally,
23% of cycles with an LH-to-FSH ratio of 0.60 exhibited a
premature increase in P, which was significantly higher
than the 0.30-to-0.60 ratio (P¼.03; RR ¼ 1.1, 95% CI
1.0–1.3) (Fig. 1).
Response Group Outcomes
When the analysis was performed for the 18 groups, differ-ences
between each group were also evident. Cycles using
absolutely no exogenous LH had the highest risk of a prema-ture
increase in P, as mentioned previously, with 40% hav-ing
a P level R1.5 ng/mL at the end of stimulation,
significantly higher than all other subgroups (P.001; RR
¼ 2.0, 95% CI 1.8–2.2). However, extremes of stimulation,
both high and low, were associated with significant risk
for a late increase in P. Specifically, patients with ratios of
exogenous LH-to-FSH that deviated the furthest from the
lowest risk range had the most substantial increase in P.
In the subanalysis, where differing response groups were
analyzed, the critical breakpoints identified from the receiver
operator characteristic curve were applied and the same
pattern appeared. Overall, the percentage of patients with a
premature increase in P was significantly different among
response groups (P.001); highest in high response at 37%
risk, intermediate in normal response at 22% risk, and lowest
in low response at 11% risk. The lowest risk of a premature in-crease
in P was noted in the seven groups spanning the LH-to-
FSH ratio ranges of 0.30–0.60 (Fig. 2).
Similar to the large group analysis patients using no LH in
their stimulation had the greatest risk of a premature increase
in P when compared with all other LH-to-FSH ratios. This risk
was 32% in the normal response group and 57% in the high
response groups (P.001). This analysis was not applicable
to the low response group, as only one cycle did not include
exogenous LH. Similar to the entire cohort, cycles with LH-to-
FSH ratios that deviated furthest from the optimal range
had the most substantial increases in P.
Logistic regression was used to model the relationship be-tween
the LH-to-FSH ratio and a premature increase in serum
PR1.5 ng/mL. Subjects with an LH-to-FSH ratio between 0.3
and 0.6 were less likely to have an elevated serum P on the day
of trigger (odds ratio [OR] ¼ 0.5, 95% CI 0.45–0.55; P.001).
When controlling for the number of follicles 14 mm, stim-ulation
protocol, serum E2 on the day of trigger, and diagno-ses
of polycystic ovary syndrome (PCOS) and diminished
ovarian reserve, this relationship persisted (OR ¼ 0.42, 95%
CI 0.38–0.47; P.001).
DISCUSSION
Increasing evidence during the past several years has
confirmed that late follicular elevations in P during IVF stim-ulation
predict suboptimal clinical outcomes after fresh ET (8,
14, 15). For example, it has been recently demonstrated that
an increase in P R1.5 ng/mL before hCG administration
was the critical threshold at which clinical outcomes were
diminished in one large assisted reproductive technology
(ART) program (1). The results of the present study provide
insight into an iatrogenic cause of a late follicular increase
in P, and possibly a way to protect against this adverse effect.
The most likely explanation for the adverse impact of this
effect relates to advancement of endometrial receptivity re-sulting
from a premature secretory transformation due to
supraphysiologic serum P levels (16). The question remains
whether clinical management decisions impact these late P
increases and whether there are specific interventions that
would reduce risk. One option would be to trigger final oocyte
maturation early during stimulation (17); however, it is diffi-cult
to predict when P will cross a critical threshold that im-pairs
receptivity and this may also result in a suboptimal
yield of mature oocytes at retrieval. Although routine cryo-preservation
of the cohort of embryos has been proposed,
this introduces an intervention and delay in pregnancy for
a majority of patients who would otherwise have favorable
FIGURE 1
The incidence of late follicular increase in P is significantly lower in
cycles with an administered LH-to-FSH ratio between 0.30 and
0.60. P.001 for FSH only to 0.30–0.60; P.001 for 0–0.30 to
0.30–0.60; P¼.03 for 0.30–0.60 to 0.60.
4 VOL. - NO. - / - 2014

outcomes with a fresh ET. If there were a way to reduce the
risk of late P elevations, this could provide an opportunity
for a higher proportion of patients to undergo fresh ET
without being subjected to the adverse impact of premature
P increases.
The purpose of the current study was to determine
whether the risk of significant premature P increase is related
to one of the most fundamental clinical decisions made by
reproductive endocrinologists during IVF stimulation,
namely the composition of the gonadotropins administered.
When analyzing an extremely large dataset of more than
10,000 IVF cycles, it was determined that in fact the dosing
decisions made by clinicians do impact the risk of premature
P increase and these data point to a method to reduce this risk:
including an adequate proportion of LH activity during
stimulation.
Because pituitary LH is the signal that initiates follicular
luteinization with the accompanying massive production of
P, it seemed intuitive that excessive exogenous LH in stimu-lation
may have a similar effect, thus driving up serum
P levels. This prompted the development of pure FSH prepara-tions
and a shift in clinical practice to prescribe FSH-only pro-tocols.
The results of the Menotropin versus Recombinant FSH
in vitro Fertilization Group (MERIT) trial, which compared
serum and follicular P levels, at first appeared counterintui-tive
(9). Patients randomized to receive pure FSH actually
had higher P levels than those receiving hMG-only protocols.
In light of the two-cell, two-gonadotropin theory, as
described previously, this should not have been so surprising
(18). Excessive FSH stimulation may increase production of P
and other precursors from the granulosa cells (GC). Therefore,
including some LH in stimulation protocols to counterbalance
the effect of FSH may help reduce the risk of late follicular P
increases.
These analyses reveal that variations in the relative pro-portion
of LH and FSH administered have a substantial impact
on the outcomes of ovarian stimulation. A ratio of LH-to-FSH
Fertility and Sterility®
that falls between 0.30 and 0.60 during the cycle provides the
lowest risk of a premature increase in P and represents a target
‘‘sweet spot’’ for clinicians. This relationship holds true for low
responders, normal responders, and high responders. Howev-er,
it is notable that high responders had the greatest risk of a
premature increase in P when compared with all other groups.
It is important to note that in this analysis, only the absolute
level of P was considered, not the relative proportion of E2 to P
or P per mature follicle. A likely explanation for this increased
risk in high responders relates to a cumulative effect of many
follicles producing small amounts of P before hCG adminis-tration.
Significantly, this population still had the lowest
risk of P elevation when their LH-to-FSH ratio decreased
within the 0.30–0.60 range.
Interestingly, extremes of stimulation that deviated the
furthest from the optimal ratio, or sweet spot, of 0.30–0.60,
were at the greatest risk of a premature increase in P. The rela-tive
risk of premature P increase was more pronounced in the
lower ranges of the LH-to-FSH ratio spectrum than the .60
range.
These data suggest that the clinician can influence stim-ulation
outcomes and protect against a premature increase in
P by providing an appropriate amount of exogenous LH in
stimulation to ensure thecal conversion of P to androgen pre-cursors.
Stimulations using no exogenous LH had the highest
risk of a premature increase in P and this finding confirms re-sults
of previous literature (8, 19). With dose modifications
during stimulation, absolute quantities of LH and FSH will
vary throughout stimulation. It is important for clinicians to
remain cognizant of this need to balance the ratio of LH-to-
FSH to prevent a late follicular increase in P.
Although there are many subtle differences in stimulation
style and gonadotropin preferences that can yield excellent
ART outcomes, the results of this large dataset may help refine
these clinical decisions. As doses are reduced during step-down
protocols, reducing the FSH component would help to
keep the total administered LH-to-FSH ratio toward the
FIGURE 2
The optimal ratio of exogenous LH-to-FSH to prevent a premature increase in P according to response group.
VOL. - NO. - / - 2014 5

middle-to-upper range of the sweet spot. For example, a start-ing
dose that provides an equivalent dose of pure FSH and
hMG (or 10 IU of low dose human chorionic gonadotropin
(LDHCG) for every 150 IU of pure FSH) would yield a ratio
of 0.50 if the dose was maintained throughout stimulation.
A slight reduction in the FSH component toward the end of
stimulation, or an equal reduction of FSH and hMG together,
would keep the total administered gonadotropin ratio within
the desired range.
In this analysis both LDHCG and hMG were included as
sources of exogenous LH exposure. Very few cycles incorpo-rated
recombinant LH. These preparations have different phar-macodynamics
and a study comparing individual outcomes
would be beneficial. The high risk population of patients
with diminished ovarian reserve, who have an increased risk
of late follicular P increases due to ‘‘premature luteinization,’’
often receive microdose GnRH agonist flare protocols in this
center and, therefore, were not included. Consequently these
results may not be generalizable to this population.
A limitation of this study relates to its retrospective
design. Although differences in risk were found consistently
in the different LH-to-FSH ratios and these were consistent
across age groups, this type of study cannot definitely prove
that changing management in another population prospec-tively
would improve endocrine dynamics during stimulation.
The extremely large sample size, however, provides excellent
precision regarding the risk of P increase in the different
groups of LH-to-FSH ratio and ovarian response. Another
confounding variable, which may limit generalized applica-tion,
is that this analysis only reports total LH-to-FSH ratios
during the entirety of a cycle rather than starting or changing
doses. This ratio was chosen as the most accurate representa-tion
of total gonadotropin dosage due to practice standards
where gonadotropin dosages remain relatively constant
throughout cycles. In addition, this large dataset could correct
for potential sources of bias such as preferences of individual
physicians within a large group practice.
This study provides insight into the importance of exog-enous
LH in stimulation and the necessity to include LH activ-ity
to balance the deleterious effects of excessive exogenous
FSH. The exclusion of exogenous LH in stimulation is iatro-genic,
not physiologic, and may impair IVF outcomes by
significantly altering the endocrine milieu and placing pa-tients
at an increased risk of premature secretory transforma-tion
and decreased endometrial receptivity at the time of ET.
There appears to be a role for exogenous LH for all types of
ovarian responders. Relative doses outside the sweet spot ratio
of 0.30-to-0.60 are associated with the highest risk of a pre-mature
increase in P that may translate into poorer overall
outcomes and diminished clinical PRs.
Acknowledgments: The authors thank Batsal Devkota for
his assistance in data collection of the Reproductive Medicine
Associates of New Jersey Bioinformatics team.
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6 VOL. - NO. - / - 2014

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