luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight...

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: [email protected]

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.



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.



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.




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.



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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8 L. W. Roth et al.

luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight...

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