luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight...
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O R I G I N A L A R T I C L E
Luteal phase dynamics of follicle-stimulating and luteinizinghormones in obese and normal weight women
Lauren W. Roth*, Amanda A. Allshouse†, Erica L. Bradshaw-Pierce‡, Jennifer Lesh*, Justin Chosich*,
Wendy Kohrt§, Andrew P. Bradford¶, Alex J. Polotsky* and Nanette Santoro*
*Division of Reproductive Endocrinology and Infertility, University of Colorado, †Department of Biostatistics and Informatics,
University of Colorado, ‡Department of Pharmaceutical Sciences, University of Colorado, §Division of Geriatric Medicine,
University of Colorado, and ¶Division of Basic Reproductive Sciences, University of Colorado, Denver, CO, USA
Summary
Objectives Female obesity is a state of relative hypogonado-
trophic hypogonadism. The aim of this study is to examine
gonadotrophin secretion and response to gonadotrophin-releas-
ing hormone (GnRH) in the luteal phase of the menstrual cycle
and to investigate the pharmacodynamics and pharmacokinetics
of endogenous and exogenous luteinizing hormone (LH) in
obese women.
Design Participants underwent a luteal phase frequent blood
sampling study. Endogenous LH pulsatility was observed, gonad-
otrophin-releasing hormone (GnRH) was given in two weight-
based doses, and GnRH antagonist was administered followed
by recombinant LH.
Patients Regularly menstruating obese (n = 10) and normal
weight (n = 10) women.
Measurements Endogenous hypothalamic-pituitary function
(as measured by LH pulsatility), pituitary sensitivity (GnRH-
induced LH secretion), pharmacodynamics of endogenous LH
and pharmacokinetics of exogenous LH were compared between
the obese and normal weight groups.
Results There were no statistically significant differences in
endogenous LH pulsatility or pituitary responses to two weight-
based doses of GnRH between the obese and normal weight
women. There were no differences in the pharmacodynamics of
endogenous LH or the pharmacokinetics of exogenous LH
between the groups. FSH dynamics did not differ between the
groups throughout the study.
Conclusions The relative hypogonadotrophic hypogonadism of
obesity cannot be explained by differences in LH and FSH luteal
phase dynamics or differences in endogenous LH pharmacody-
namics or exogenous LH pharmacokinetics.
(Received 19 November 2013; returned for revision 10 December
2013; finally revised 4 February 2014; accepted 24 February 2014)
Introduction
Approximately 20% of reproductive-aged women are obese.1
Obesity has a multitude of negative effects on health,2 including
a number of negative consequences on reproduction.3
Excess body weight is associated with a state of relative hy-
pogonadotrophic hypogonadism in both sexes.4–11 Luteinizing
hormone (LH) pulse amplitude is lower in obese men4 and ovu-
latory obese women in the follicular phase5 compared to normal
weight controls. Additionally, whole menstrual cycle LH,6,10
whole cycle and follicular phase follicle-stimulating hormone
(FSH),6,7,10 and whole cycle progesterone5,6,10 are significantly
lower in ovulatory obese versus normal weight women. Obesity
has also been associated with decreased levels of sex steroids in
both sexes.7,9
The physiology behind the relative hypogonadotrophic hyp-
ogonadism of obesity is not fully understood. Although previ-
ous studies point to a defect in LH pulsatility,5 other areas of
the hypothalamic-pituitary axis remain underexplored. Obesity
is associated with an increase in blood volume (doubling of
BMI results in a 30% increase in blood volume) that could
lead to a relative dilution of hormone concentrations.12,13
Pharmacokinetics of gonadotrophins have not been explored
in ovulatory obese women; however, obese men have been
shown to exhibit increased clearance of LH compared to
normal weight men.14 Although it is unlikely that gonadotro-
phins are sequestered in fat, lipophilic sex steroids (i.e. pro-
gesterone) might be13,15,16 and this sequestration could be a
source of sustained negative feedback on the hypothalamus
and pituitary.
Decreased LH pulsatility has been illustrated in the follicular
phase in ovulatory obese women5, but gonadotrophin dynamics
have not been evaluated in the luteal phase. We chose to
investigate the luteal phase because it has not been characterized
in ovulatory obese women. Additionally, low luteal phase
Correspondence: Lauren W. Roth, 3055 Roslyn St, Ste 230, Denver, CO80238, USA. Tel.: +1 303 724 8089; Fax: +1 303 724 8149;E-mail: Lauren.Roth@ucdenver.edu
Clinical trial registration number: NCT01457703, www.clinicaltrials.gov
© 2014 John Wiley & Sons Ltd 1
Clinical Endocrinology (2014) doi: 10.1111/cen.12441
pregnanediol glucuronide (Pdg, a urinary progesterone metabo-
lite) excretion seen in ovulatory obese women5 may be second-
ary to inadequate luteal phase LH pulsatility. The slower LH
pulses in the luteal phase allow for GnRH stimulation testing
with a lower chance of endogenous LH pulsatility interfering
with the results.
The aims of this investigation are to (i) examine the pattern
of gonadotrophin secretion and response to GnRH in the luteal
phase of the menstrual cycle of obese women and (ii) investigate
the pharmacodynamics and pharmacokinetics of endogenous
and exogenous LH in obesity. Endogenous LH pulsatility was
observed as an indicator of endogenous hypothalamic-pituitary
function of obese compared to normal weight women. Gonado-
trophin-releasing hormone (GnRH) was given in two
weight-based doses spanning the physiologic range17 to compare
pituitary sensitivity (GnRH-induced LH secretion) between
obese and normal weight women. Finally, pharmacodynamics of
endogenous LH were evaluated during the unstimulated study
and after GnRH administration. Pharmacokinetic differences
were evaluated after GnRH antagonist followed by recombinant
LH administration to evaluate possible differences in clearance
of exogenous LH. We hypothesized that the relative hypogona-
dotrophic hypogonadism previously seen in ovulatory obese
women in the follicular phase of the menstrual cycle would hold
true in the luteal phase.
Materials and methods
Participants
Regularly menstruating obese (n = 10) and normal weight
(n = 10) women were recruited from the community through
campus-wide advertisement from August 2011 through Septem-
ber 2012. Inclusion criteria were as follows: (i) age 18–40 years;
(ii) obese (≥30 kg/m2) or normal (18–25 kg/m2) BMI; (iii) his-
tory of regular menses every 25–40 days; (iv) normal baseline
prolactin, thyroid-stimulating hormone (TSH) and blood count.
Participants were excluded if they had a chronic disease or used
medication known to affect reproductive hormones, used exoge-
nous sex steroids within the last three months, exercised more
than four hours weekly or were attempting pregnancy. All par-
ticipants had a baseline physical examination by study personnel
and underwent all blood tests at the Clinical and Translational
Research Center (CTRC) of the University of Colorado School
of Medicine’s Clinical and Translational Sciences Institute
(CCTSI). A comprehensive metabolic panel (CMP) and serum
pregnancy test were performed, with the CMP repeated at the
end of the study.
Two obese participants were excluded from further analysis as
outliers. Their LH values throughout the frequent blood sam-
pling were found to be >2 standard deviations above the mean
for all participants. Both had increased serum testosterone levels,
indicative of polycystic ovary syndrome.
The study was approved by Colorado Multiple Institutional
Review Board, and signed informed consent was obtained from
each participant prior to participation.
Protocol
A pictorial overview of the protocol is shown in Fig. 1. A two-
day frequent blood sampling study was scheduled 6–10 days
after a commercially available urinary LH kit indicated that an
ovulatory LH surge was about to occur. On the day of their fre-
quent sampling study, all participants underwent a transvaginal
ultrasound to assess antral follicle count and check for the pres-
ence a corpus luteum. FSH, LH and anti-M€ullerian hormone
(AMH) were also checked the day of the frequent sampling
study. Day 1 of the study consisted of 12 h of unstimulated, fre-
quent blood sampling at 10-min intervals. This was followed by
administration of GnRH 25 ng/kg intravenously (IND 7420).
Two hours later, GnRH 150 ng/kg was given followed by 2 more
hours of frequent blood sampling. GnRH antagonist (cetrorelix
3 mg subcutaneously, Cetrotide� EMD Serono, Rockland, MA,
USA) was given at the end of day 1, and the participant slept
undisturbed in the inpatient CTRC of the CCTSI until 8 am of
the following morning. Day 2 consisted of a 6-h frequent blood
sampling study after intravenous administration of a physiologic
dose of recombinant LH (lutropin alfa 12�5 IU, Luveris� EMD
Serono). All participants also underwent a dual-energy X-ray
absorptiometry scan (DXA) (Hologic Discovery W, Bedford,
MA, USA, Apex 4�0�1) after completing the frequent blood sam-
pling study to evaluate body composition.
Hormone assays
Luteinizing hormone and FSH were measured with immunoflu-
orometric assays (DELFIA, Perkin-Elmer, Waltham, MA, USA)
that have been used previously in the authors’ laboratory. The
LH intra-assay coefficient of variation (CV) ranged from 2�86 to
4�05%, and the interassay CV ranged from 2�62 to 4�68%. The
FSH intra-assay CV range was 4�70–5�28%, and the interassay
CV range was 4�01–8�22%.
Oestradiol, oestrone, progesterone and testosterone were mea-
sured with immunoassay (Siemens, Munich, Germany, Centaur
XP). Intra-assay and interassay CVs are as follows: oestradiol
3�7%, 10�6%, oestrone 6�4%, 11�7%, testosterone 1�6%, 3�7%and progesterone 2�6%, 3�6%.
Fig. 1 Study protocol.
© 2014 John Wiley & Sons Ltd
Clinical Endocrinology (2014), 0, 1–8
2 L. W. Roth et al.
Anti-M€ullerian hormone was measured with AMH Gen-2
ELISA (Beckman Coulter, Brea, CA, USA). Intra-assay CVs ranged
from 4�7 to 6�0%, and interassay CVs ranged from 5�2 to 6�3%.
Pulsatile characterization
Luteinizing hormone pulsatility was evaluated using a modified
Santen-Bardin method as described previously.5,18 A blinded set
of 72 samples of the same serum has been previously run for
LH and FSH and subjected to pulsatile hormone analysis using
the same gonadotrophin assay and pulse detection method. One
false-positive, low-amplitude LH pulse was detected (0�8 IU/ml),
and no false-positive FSH pulses were detected.
Pharmacokinetic analysis
LH data were evaluated by noncompartmental analysis with
Phoenix WinNonlin (version 6�2�1, Pharsight, St. Louis, MO,
USA). Exposure was determined by calculating the area under
the LH concentration–time curve (AUC0?t) by the trapezoidal
rule and calculated for given time intervals: 0–710 min for base-
line; 720–830 min for GnRH 25 ng/kg; 840–960 min for GnRH
150 ng/kg; and 1440–1670 min for Luveris. The elimination
half-life (t½) of LH was determined from the elimination phase
following Luveris administration.
Statistical methods
An a priori sample size estimate was performed using follicular
phase LH pulse amplitude from a prior study5 as the measure of
interest. With 10 patients in each group, 90% power was present
to detect a difference of 0�59 IU/l in LH pulse amplitude using a
two-sample t-test and alpha of 0�05.Endogenous LH was modelled over time by group using a lin-
ear mixed-effects model to use every observation from each par-
ticipant while accounting for similarities within person. Patient-
level characteristics of endogenous LH pulsatility (patient pulse
and amplitude), patient-average LH and FSH, patient-level phar-
macokinetic parameters (AUC, t1/2) and DXA measures were
compared using t-tests or Mann–Whitney tests. Biometric
parameters (DXA and anthropometric measurements) and
patient-level hormone values (baseline LH, total AFC and AUC
within each phase) were compared graphically and using Pear-
son’s correlation coefficient. Results of statistical analysis are
reported as mean � standard deviation if a t-test was used and
as median (25th percentile, 75th percentile) if a Mann–Whitney
test was used. P < 0�05 was considered statistically significant.
Analysis was conducted using SAS software (v9�2 9 64 platform;
SAS, Cary, NC, USA).
Results
Participant sample characteristics
Demographic data are shown in Table 1. The obese women were
significantly older than the normal weight women (32�5 � 4�7 vs
27�3 � 2�6 years, P = 0�006). FSH, anti-M€ullerian hormone levels
(AMH) and antral follicle counts (AFC), all markers of ovarian
reserve,19 did not differ between the two groups. By design, the
obese group had a significantly greater BMI than the normal
weight group (34�3 (31�8, 38�9) vs 22�3 (21�1, 22�8) kg/m2,
P < 0�001). As expected, obese women had a significantly greater
waist and hip circumference than the normal weight women. The
groups did not differ in terms of race or ethnicity, with the major-
ity of participants being Caucasian and non-Hispanic.
Endogenous LH and FSH secretion
Figure 2a is a composite graph showing mean circulating LH
for the unstimulated portion of the frequent blood sampling
study, representing endogenous luteal phase LH pulsatility.
Figure 2b is a raw and linear mixed-effects model of endogenous
LH; age was considered for inclusion in modelling, however was
not itself significant and did not alter conclusions. A linear
mixed-effects model allows us to use every observation from
each participant while accounting for similarities within person.
Although the obese group had a lower average LH at every point
in time, LH was not statistically significantly different between
BMI groups. Additionally, the groups did not differ with respect
to mean LH, pulse frequency or pulse amplitude (Table 2a).
Table 1. Demographic information
Obese
n = 10
Normal
weight n = 10 P
Age (years) 32�5 � 4�7* 27�3 � 2�6 0�006Race
Caucasian 4 (40)† 9 (90) 0�08African American 3 (30) 0 (0)
Other/not reported 3 (30) 1 (10)
Ethnicity
Hispanic 1 (10) 2 (20) 1�0Non-Hispanic 9 (90) 8 (80)
Body mass index
(kg/m2)
34�3 (31�8, 38�9)‡ 22�3 (21�1, 22�8) <0�001
Waist (cm) 104 � 11 78�2 � 6�3 <0�001Hip (cm) 114 (104�3, 128) 92�5 (90, 98) <0�001FSH 3�8 (2, 4�2) 3�3 (3, 4�9) 0�7Anti-M€ullerian
hormone (ng/dl)
1�6 (0�6, 6�2) 5�4 (1�8, 10�3) 0�1
Antral follicle count 16�5 (12, 41�4) 23 (15�7, 50�7) 0�2Oestradiol (pg/ml)§ 374 � 146 388 � 113 0�8Oestrone (pM)§ 1301�9 � 913�6 1642�2 � 525�2 0�3Progesterone (nM)§ 25�76 � 11�45 18�76 � 16�85 0�3Testosterone (nM)§ 1�21 � 0�70 1�1 � 0�46 0�5Preprandial insulin
(mU/l)
5�8 � 3�0 3�5 � 1�6 0�05
Random glucose
(mg/dl)
6�1 � 1�2 5�2 � 1�09 0�02
*Mean � standard deviation.
†frequency (percentage).
‡Median (25th percentile, 75th percentile).
§serum pooled from unstimulated frequent sampling study.
© 2014 John Wiley & Sons Ltd
Clinical Endocrinology (2014), 0, 1–8
Luteal phase FSH and LH dynamics 3
Mean FSH, measured hourly, did not differ between the groups
(Table 2a). There was a moderate correlation between AFC and
baseline LH, q=0�49, P = 0�03.
GnRH-stimulated LH secretion
Figure 3 shows the composite LH responses to two weight-based
doses of GnRH. The first dose of GnRH (25 ng/kg) is considered
slightly subphysiologic 17, and the second dose of GnRH (150 ng/
kg) is considered slightly supra-physiologic.17 There were no
significant differences in the LH concentration–time curves
(AUC0?t) following either dose of GnRH in obese compared to
normal weight women. Peak LH, LH increment and time to peak
LH did not differ between the groups after either dose of GnRH.
There was a moderate correlation between AFC and response to
GnRH 150 ng/kg, q = 0�47, P = 0�04.
Exogenous LH disappearance
Figure 4 shows the composite LH levels 8 h after suppression
with GnRH antagonist (cetrorelix 3 mg) and administration of
recombinant LH (Luveris 12�5 mg). There were no differences
between the groups with respect to mean LH, peak LH or time
to peak LH.
Pharmacodynamics of endogenous or exogenous LH
Pharmacodynamics of endogenous and exogenous LH, as mea-
sured by LH concentration–time curve (AUC0?t), did not differ
between the groups. The half-life of exogenous LH, calculated by
linear regression, did not differ between the two groups.
Body composition analyses
DXA data are shown in Table 2b. As expected, whole body and
trunk fat mass and per cent whole body fat, trunk fat and vis-
ceral fat are significantly higher in the obese versus normal
weight group (Table 2b). Additionally, whole body and per cent
whole body lean mass are significantly lower in the obese versus
normal weight women. There was no correlation between any
Table 2. (a) Characteristics of endogenous luteinizing hormone
pulsatility. (b) DXA results
Obese Normal weight P
(a)
Mean LH 4�1 (2�9, 5�2)* 3�6 (2�7, 9�9) 0�8LH pulses per hour 0�3 � 0�1† 0�3 � 0�2 0�6LH pulse amplitude 4�4 (2�8, 7�6) 5 (3�5, 7�1) 0�5Mean FSH 3�8 (2�1, 4�2) 3�3 (3, 4�9) 0�7
(b)
Whole body fat mass
(gm)
39 667 � 6988 17 199 � 2540 <0�001
Percent whole body
fat (%)
41�8 � 3�1 27�5 � 2�3 <0�001
Whole body lean mass
(gm)
55 001 � 7427 45 346 � 4986 0�004
Percent whole body
lean (%)
58�2 � 2�9 72�5 � 2�2 <0�001
Trunk fat mass (gm) 19 862 � 3909 7037 � 1516 <0�001Percent trunk fat (%) 42�3 � 3 24 � 3�6 <0�001Percent visceral fat (%) 50�1 � 4�5 40�7 � 3�9 <0�001
*Median (25th percentile, 75th percentile).
†Mean � standard deviation.
(a) (b)
Fig. 2 (a) Composite of mean endogenous luteinizing hormone (LH) (� SEM). (b)Raw and linear mixed-effects model of endogenous LH; normal
weight: blue, obese: red. The dashed lines show each participant’s results, and the bold line was estimated using the linear mixed-effects model.
© 2014 John Wiley & Sons Ltd
Clinical Endocrinology (2014), 0, 1–8
4 L. W. Roth et al.
DXA measurement and unstimulated LH, GnRH-stimulated LH
response or exogenous LH pharmacokinetics.
Discussion
We used luteal phase sampling to examine LH dynamics to take
advantage of a slowed endogenous GnRH pulse generator,20
because we intended to administer exogenous GnRH as part of
our experimental characterization. However, in contrast to our
previous observations in the follicular phase,5 luteal phase differ-
ences in mean LH and LH pulse amplitude were not seen.
Response to two exogenous GnRH doses spanning the physiologic
range17 was not significantly different by weight. The obese group
had relatively consistent responses to GnRH and exogenous LH,
and their luteal phase LH secretory patterns were similarly consis-
tent. However, the normal weight group displayed wide variation
in their endogenous LH pulsatility and in their responses to exog-
enous GnRH and LH and thus accounted for a great deal of the
variability that obscured an ability to distinguish between the two
groups. This degree of variation was somewhat surprising, as we
had not seen it in our prior studies.5 There were no correlations
between DXA measurements and endogenous LH, response to
GnRH or response to exogenous LH.
Importantly, we did not observe any differences between obese
and normal weight women in pharmacodynamics or pharmaco-
kinetics of either endogenous or exogenous recombinant LH.
This finding implies that obesity per se does not affect
post-translational processing of the LH molecule, nor does obes-
ity appear to cause circulating LH to be lower because of factors
such as volume of distribution. While there is no reason to
expect sequestration of LH into adipose tissue, it is possible that
progesterone may be taken up by the fat tissues of obese
women, thereby lowering circulating progesterone.12,13 Taken
together, the data suggest that if circulating LH is distributed in
a larger plasma volume in obese women, secretion keeps pace
with this increased volume of distribution to maintain the
reproductive system in equilibrium. The lack of difference in
pharmacodynamics and pharmacokinetics of LH contrasts with
a study in obese men that found the endogenous LH half-life to
be significantly shorter in obese versus normal weight men and
implies that LH clearance may differ between the sexes.14 Srouji
et al. investigated endogenous and recombinant LH pharmacoki-
netics in women with PCOS and, similar to our results, found
no differences in recombinant LH pharmacokinetics based on
BMI.21 However, the obese women with PCOS had accelerated
clearance of endogenous LH as evidenced by a decreased half-
life.21 It is possible that the former studies were performed
against a background of relatively rapid LH pulse frequency
making it difficult to follow individual endogenous LH pulses
long enough to calculate robust LH disappearance curves. Thus,
our luteal phase sampling paradigm is uniquely valuable for this
purpose.
Fig. 3 Composite luteinizing hormone response to gonadotrophin-releasing hormone (GnRH) 25 ng/kg (small arrow) and GnRH 150 ng/kg (large
arrow), mean � standard error.
© 2014 John Wiley & Sons Ltd
Clinical Endocrinology (2014), 0, 1–8
Luteal phase FSH and LH dynamics 5
In this study, GnRH was given to investigate pharmacokinet-
ics of endogenous LH, thereby bypassing the typical kisspeptin-
controlled pituitary GnRH secretion.22 There is some evidence
that obesity decreases kisspeptin via decreased leptin.23–26
Decreased kisspeptin would decrease GnRH resulting in
decreased gonadotrophin secretion as seen in the follicular
phase.5,10 However, decreased gonadotrophins in the obese
group were not illustrated in this study.
The lack of difference between obese and normal weight
women with respect to luteal LH pulse amplitude was unex-
pected, as a difference has been repeatedly shown in the follicu-
lar phase.5,10 The subfertility associated with the relative
hypogonadotrophic hypogonadism of obesity is believed to be
secondary to luteal phase deficiency27 and to originate from a
relative deficiency of follicular stimulation in the first half of the
menstrual cycle such that a poorly cultivated follicle leads to a
poorly functioning corpus luteum. However, most overweight
and obese women are fertile, and although there are hormonal
alterations in the follicular phase5,10, our results suggest that
those differences do not carry over into the luteal phase. This
makes sense biologically as the corpus luteum is necessary for
pregnancy28 and therefore for carrying on reproduction of the
human race. It is possible that the defect in LH secretion and
pituitary response to GnRH is limited to the follicular phase.
This is supported by Legro et al., who showed that the most
notable change in menstrual function and hormone parameters
in the setting of extreme weight loss after bariatric surgery was a
shortening of the follicular phase.29 Additionally, our group
previously found that obese women had a lower mean LH in
the follicular phase compared with normal weight women, but
no difference in mean LH was seen over an entire menstrual
cycle.5
It is noteworthy that the obese group was significantly older
than the normal weight group (mean age obese 32�5 vs normal
weight 27�3 years), and this could impact their gonadotrophin
parameters. Despite their age difference, the obese groups’ ovar-
ian reserve parameters (FSH, oestradiol, AMH and antral follicle
counts) did not differ in comparison with the normal weight
group making it less likely that diminished ovarian function
played a role in the results of this study. AMH is the most useful
ovarian reserve parameter30–32 and did not differ significantly
between the groups. This is consistent with a large study investi-
gating age-specific AMH values for over 17 000 women showing
the average decrease in AMH between ages 27 (the mean age of
our normal weight group) and 32 (the mean age of our obese
group) was 1�0 ng/ml.33 Additionally, the study findings did not
change when age was taken into account for statistical modelling.
It is important to note that the obese group of women that
we studied had neither clinical nor biochemical evidence of
polycystic ovary syndrome (PCOS). Aside from having regular
cycles, their antral follicle counts, circulating testosterone and
AMH levels were normal.34 In fact, the obese group had a lower
AMH than the normal weight group (though not statistically
significantly so). Women with PCOS have been reported to
have increased AMH levels,35,36 whereas recent observations of
ovulatory obese women without PCOS indicate that AMH is
Fig. 4 Composite mean luteinizing hormone (LH) after gonadotrophin-releasing hormone suppression and administration of recombinant LH (purple
arrow), mean � standard error.
© 2014 John Wiley & Sons Ltd
Clinical Endocrinology (2014), 0, 1–8
6 L. W. Roth et al.
lower in this state (as seen in this study).37–39 The obese women
had higher random glucose levels and preprandial insulin levels
compared to the normal weight women. Insulin levels increase
with body weight40, but the obese women in this study are not
insulin resistant.41
It is also noteworthy that the obese group’s oestradiol, oestrone
and progesterone levels did not differ from the normal weight
group. Similar oestradiol and oestrone levels indicate that negative
feedback from increased circulating oestrogens is not the cause for
the relative hypogonadotrophic hypogonadism of obesity. Many
observations linking obesity to increased circulating oestrogens
are derived from data in postmenopausal women,42,43 thus not
taking into account the role of ovarian oestradiol production. In
regularly cycling women, it appears that the ovary produces much
higher levels of oestrogens than does adipose tissue, such that any
adipose contribution to the total oestrogen pool is minor.
Although prior studies report poor Pdg excretion in obese
women,5,10 no difference in serum progesterone levels between the
groups was seen in the present study.
Hypothalamic dysfunction does not appear to play a role in
the hypogonadotrophic hypogonadism of obesity, as LH pulse
frequency is preserved and luteal phase LH pulse amplitude may
not be affected by obesity. Additionally, the pharmacodynamics
and pharmacokinetics of endogenous and exogenous LH are not
different between obese and normal weight women. It may be
that, by the time ovulation has occurred, the pathophysiologic
events responsible for subfertility have already taken effect, and
thus, it is more difficult to locate the hypothalamic-pituitary-
ovarian axis defect(s) responsible for the problem in the luteal
phase. There may also be inadequate LH to progesterone
throughput, such that the ovarian response to an equivalent LH
pulse produces less progesterone in an obese compared to a nor-
mal weight woman. Alternatively, other, nonsteroidogenic fac-
tors secreted by the corpus luteum may contribute to the
adverse reproductive phenotype of obesity.
In summary, the relative hypogonadotrophic hypogonadism
associated with obesity may not be caused by differences in
luteal phase LH pulsatility, pituitary response to GnRH or dif-
ferences in endogenous and exogenous LH pharmacokinetics.
Acknowledgements
NIH U54HD058155 Center for the Study of Reproductive
Biology (NS), NIH/NCRR Colorado CTSI Grant Number UL1
RR025780. Contents are the authors’ sole responsibility and
do not necessarily represent official NIH views. (NS) Univer-
sity of Colorado Cancer Center Grant P30 CA046934 (EBP).
LWR received Clinical Research Fellowship and Mentor Award
Supported by Pfizer, Inc. for research presented at ENDO
2012 and an ASRM Corporate Member Council In-training
Travel Award for research presented at IFFS/ASRM 2013. AJP
receives investigator-initiated grant support. NS has stock
options in Menogenix and receives investigator-initiated grant
support. AAA, ELB, JL, JC, WK and APB have no disclosures
to report. This research was presented at the 94th annual
meeting of the Endocrine Society in Houston, TX, 23–26 June
2012.
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