Mild hypogonadotropic hypogonadism in obese men

Mild hypogonadotropic hypogonadism in obese men

Mild Hypogonadotropic Gladys W. Strain, Barnett Zumoff, Robert S. Rosenfeld, Hypogonadism Jacob Kream, in Obese Men James J. Strain, Richard Deuc...

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Mild Hypogonadotropic Gladys W. Strain,

Barnett Zumoff,

Robert S. Rosenfeld,

Hypogonadism Jacob Kream,

in Obese Men

James J. Strain, Richard Deucher,

Joseph Levin, and David K. Fukushima

To evaluate the pituitary-gonadal axis of obese men, we compared the 24-hour mean plasma concentrations of total and free testosterone and of dihydrotestosterone, FSH, and LH in 21 healthy obese men, aged 18-50, and 24 age-matched healthy nonobese men. In the obese men, we also measured the volume of ejaculate and the number and motility of sperm, and potency by history and by measurement of nocturnal penile and investigated libido by psychiatric interview, tumescence. As a group, the obese men had less than two-thirds the normal mean plasma levels of total testosterone. free testosterone, and FSH; the difference from normal was highly significant for all three. 24 hr LH levels were normal, which is inappropriately low in view of the subnormal testosterone levels. 24 hr mean levels of dihydrotestosterone and spermatogenesis, libido, and potency were essentially normal. Taken together, the findings represent a state of mild hypogonadotropic hypogonadism. which thus appears to be characteristic of obese men. This abnormality probably results from partial suppression of the pituitary by the elevated plasma estrogen levels we and others find in these men.

T

HERE HAVE BEEN many studies of the pituitary-gonadal axis in obese women, stimulated by the readily observable menstrual irregularities and fertility problems that many of these women have, but the pituitary-gonadal axis of obese men has received less attention, possibly because these men lack obvious clinical stigmata that might point to reproductive dysfunction. Obese men have been reported by two groups to have elevated plasma estrogen levels,’ ’ and we have confirmed this finding.” There has been one report” of subnormal testosterone production, and four groups’.’ ‘” have reported subnormal plasma total testosterone levels in obese men; three of the latter groups’.‘,“’ report free testosterone levels: one’ reports normal levels; one’ reports an inverse correlation between the levels and the degree of obesity, with subnormal levels in 2 out of 10 men; and the third’” reports significantly subnormal levels in men more than I OO’Xabove desirable weight. The plasma gonadotropin levels of obese men have been reported in six studies:‘,’ ” one of these’ reports subnormal FSH levels in some of the men and the others’,‘.’ ” report normal levels; however, one of the latter’ points out that the fact that gonadotropin levels are not elevated in the face of subnormal testosterone levels means that obese men in general have depressed pituitary function. So far as we can determine, plasma dihydrotestosterone levels and sperm counts have not been reported in obese men. WC investigated the pituitary-gonadal axis of 21 otherwise healthy obese men by measuring their 24 hr mean plasma concentration of total and free testosterone. amd of dihydrotestosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and by determining the number and motility of sperm in the ejaculate. We also investigated the libido of these men. by structured psychiatric interviews, and their potency, by history and by measurement of nocturnal penile tumescence. Our findings indicate that obese men characteristically manifest a state of mild hypoMetabolrsm,

Vol. 3 1, No. 9 (September), 1982

gonadotropic and potency.

hypogonadism,

MATERIALS

but have normal

AND

libido

METHODS

Sub.jects Twenty-one

healthy

IO) and ranging 127%

)

(mean

and

obese men, aged 18-50

from

(mean

52%~-~332%8above desirable

24 age-matched

healthy

nonobese

+ SD: 33 + 14). were studied.

Informed

+ SD: 33 L weight

men.

(mean

aged

‘O-50

consent was obtained

from all subjects.

24-Hr

Mean Plasma

Hormone

These were measured

pooling aliquots determining

of

plasma

the hormone

24 hr blood-sampling

Concentrations

by sampling from

blood every 20 mitt for 24 hr. each

of the

concentrations

techniques

72 samples.

in each pool. Details

have been previously

and of the

reported

from

this laboratory.”

of’ Plasma Dih?ldrotestosterone

Determinutiorr Total

These steroids same antibody

were quantitated

rcportcd

Details

of

from this laboratory.”

rabbtts

by radioimmunoassay.

for both steriods

chromatography. agatnst

a

after

this

the testosterone procedural

assay,

taking

The addition

Research

Center.

/iw

woman

(‘enter.

in of

dose for

factors

concentration

tcstosteronc

Steriod

&on\-.

used is generated

sampling

by

previously

least detectable

to a plasma

of unlabeled

Front the Clinical and Medical

The

been

conjugate

account

oophorsctomized

try. and the Institute

have

albumin

into

using the

had been separated

The antiserum

serum

losses. is equivalent

adrenalectomi7ed

they

method

testosterone-3-carboxymethyloxime.

ng/dl.

and

Testosterorw

and

of 9-20

to plasma

from

an

at 100. 200. 400, and

the Department

Research.

of Psychia-

Montefiorr

Ho.ypitnl

N. k’.

Keceivrd Jtir publication. Supported AM-27292

in part hy Grants RR-53

from

the National

F49620-79-W)l35

front

CA-07304.

Institutes

Ck2279.5.

of‘ Health,

the L1.S. .-lir Force

und

and (‘ontract

Ofice

01 Scientific,

Research. Address Medical

reprint

Center.

requests

IO Nathan

to Dr.

Gladys

D. Perlntun

Strain,

Place.

New

Beth kbrk.

Israel N I’.

10003. 1~ 1982 by Grune & Stratton, 0026 -04U5/82/3

109~)004$

Inc. I .00/o

871

872

STRAIN ET AL.

800 pg dose levels yielded mean recoveries of lO6%, 95%, 97% and 95% respectively after correcting for procedural losses, The intraassay and interassay coefficients of variation were 7.2% (n = 20) and 13.1% (n = 14) respectively. The least detectable dose in the DHT assay is equivalent to a plasma level of 6 ng/dl. Addition of unlabeled DHT in amounts of IO pg. 20 pg. 40 pg, and 80 pg to 100 ml portions of plasma with an assayed value of 10.4 pg yielded recoveries of 8 1%. 100%. IO1 %, and 103% respectively after correction for procedural losses and subtraction of the “0” value. The intraassay and interassay coefficients of variation for a male plasma pool were 5.1% (n = 13) and 10.1% (n = 37) respectively. Determination of Plasma Free Testosterone Free testosterone is calculated using a computer program based upon the equations of Yates and Urquhart14 utilizing plasma albumin concentration, plasma SHBG determined by the method of Rosner,15 the total tesosterone concentrations, and the affinity constants for the binding of testosterone to SHBG (8.4 x IO’M ‘) and to albumin (3.7 x IO’ - Mm’) respectively. The sensitivity and variability of the determination of free testosterone are dependent upon the corresponding parameters of the assays of total testosterone, SHBG, and albumin. In our laboratory, the intra-assay and interassay coefficients of variation of the SHBG assay are 5.7% (n = 20) and 9.8% respectively. Free testosterone values calculated in this way have been shown to be essentially identical to those measured by equilibrium dialysis2’ Plasma albumin is determined by an automated procedure in the central laboratories of Montefiore Hospital, and the intra-assay and interassay coefficients of variation are both reported to be less than 5% at a range of values from 2.555.5 g/dl.

Radioimmunoassay

of Plasma FSH and LH

The methods used are the standard double-antibody procedures reported from Midgely’s laboratory.‘6,‘7 Reagents are obtained from the NPA-NIAMD as described, except for the second antibody, goat anti-rabbit-globulin, which is purchased from Pantex, Santa Monica, California. In particular, antiserum to hLH Batch #2 has been used in the studies described in this report. The relative potency (RP) of LER (in terms of the 2nd IRP HMG) using this antiserum is 2.9 ng/mlU. For the FSH assay, antiserum Batch #S was used; the corresponding RP of LER 907 is 17.5 ng/mlU. The LH antiserum cross-reacts completely with hCG. The minimum detectable dose for the LH and FSH assays are 0.4 mlU/ml and 2.9 mlU/ml respectively. In ten different assays the mean percentage of the individual tracer specifically bound to the LH antibody (final dilution 1:800,000) and to the FSH antibody (final dilution 1:250,000) was 43.6 (range 40.0-48.6) and 35.5 (range 3 I. l-44.3) respectively. The mean non-specific binding to the LH and FSH antibodies was 2.1 percent (range 1.9-2.8) and I.9 percent (range 1.5-2.0) respectively. The intra-assay variability for the LH and FSH assays was 4.1% and 6.1% respectively. The interassay variability for the LH and FSH assays was 6.7% and 10.0% respectively.

Determination of the Volume of Ejaculate and the Number and Motility of Sperm

these men by history during the interview, and was additionally evaluated in I I of them by measurement of nocturnal penile tumescence according to the method of Fisher.‘”

Statistical Methods Plasma FSH, LH dihydrotestosterone, total testosterone. and free testosterone values were distributed more nearly log-normally than normally in both obese and nonobese men. Accordingly, intergroup comparisons were made by applying Student’s t test, 2-tailed, to the logarithms of the values. The volume of ejaculate and sperm density were plotted linearly on probability paper to determine the presence of a normal distribution of values within populations.

24-Hr Mean Plasma Total and Free Testosterone The total testosterone values of the obese men were markedly subnormal (Fig. I); their geometric mean level was 268 ng/dl (95% C.L. I30 to 552). 42% lower than the geometric mean level of 461 ng/dl (95% C.L. 259 to 822) in the nonobese controls (p < 0.0001). The plasma free testosterone values showed a very close linear correlation with the total testosterone values in both the obese men and the nonobese men, and the regression lines for these two correlations did not differ significantly (/ 2.6; p = 0. I), so that the free testosterone levels of the obese men were likewise markedly subnormal (Fig. 2); their geometric mean level was 7.0 ng/dl (95% C.L. 2.9-17.0). 44% lower than the geometric mean level of 12.6 ng/dl (95% C.L. 6.9-23.1) in the nonobese controls (p i 0.001).

24-Hr Mean Plasma Dihydrotestosterone The plasma dihydrotestosterone levels of the obese men did not differ significantly from those of the nonobese controls: the geometric means were 94 and 98 ng/dl. respectively.

24-Hr Mean Plasma FSH and LH The FSH levels of the obese men were markedly subnormal (Fig. 3); their geometric mean level was 5.2 mlU/ml (95% C.L. 2.31 I .8), 36% lower than the geometric mean of 8. I mlU/ml(95% C.L. 3.8-l 7.4) in the nonobese controls (p = 0.001). The geometric mean LH level of the obese men. excluding the two clear-cut outliers designated by the symbol “x” in Fig. 4, was 10.2 mlU/ml. not significantly different from that of the nonobese controls, 10.5 mlU/ml. The two outliers had definitely subnormal values; these two men also had two of the lowest total testosterone values ( I73 and 207 ng/dl) and two of the lowest FSH values (2.9 and 3.4 mlU/ ml).

lp< : & I-, a’ ZEP 3%

960,

.

.

: 480-

0.0001~

__

$

--_

.

Ejaculates were obtained from I6 of the obese men by masturbation after 3 days of continence. Clinical urologists blind to the study design measured the volume of the ejaculate and the number of sperm (in a counting chamber); the percentage of motile sperm was estimated in all samples.

Evaluation of Libido and Potency Libido structured

was evaluated in all the obese men in the course of a interview by a psychiatrist. Potency was evaluated in all

NONOBESE

OBESE

Twenty-four-hour mean plasma total testosterone in Fig. 1. age-matched nonobese and obese men.

iYPOGONADOTROPIC

HYPOGONADISM

Ip <

IN OBESE

a73

MEN

I

0.001

24,

32

.

.

l

8

16

4 --+--

;

--=-*

12

i

.

i

l

--

a

;___

6

;

l .

X

X

3

Fig. 2. Twenty-four-hour mean plasma age-matched nonobese and obese men.

Volume of‘Ejaculate Sperm

reported

volumes

of our subjects

probability distribution

by Nelson

paper;

of sperm per ml. of

were compared

and Bunge.”

with

and Bunge plotted

show a unimodal from

Fig. 6 shows the sperm concentrations

in the ejaculates. log-normal

a unimodal

had a geometric

geometric

mean

13S.OOO.000). cantly.

mean

is normal

of 38.000,000/ml

two populations

and certainly

mal. The which

value

The

those of Nelson (95%

probably motile

normal

and those tested also had normal

Twenty

exclusively was bisexual.

gave

histories

heterosexual.

of

being

libido

in

and potency

nocturnal

sexually

two were exclusively

One 20-yr-old.

LH concentration

active:

I7

homosexual.

332% above desirable

by

penile tumeswere

and one

body weight. was

not sexually active; his size made even masturbation

diflicult.

DISCUSSION

our

(95% C.L. had a

12,000,000-

do not differ forms

plasma

men.

the obese men had essentially

Once again,

signih-

the values for the obese men were not subnor-

1~S.D. of percentage

cence.

mean

and obese

one another.

and Bunge C.L.

on

log-normal

distribution;

mean value of 46,000.000/ml while

the normal

Fig. 5 shows the ejaculate

and the two are indistinguishable

10,000,000~220,000,000)

nonobese

interview,

populations

show

Twenty-four-hour

4.

and the concentration

both

subjects

Fig.

age-matched

Libido and Poterq

and those of Nelson

both

populations

in

and Number and Motility of

in our obese population

findings

testosterone

All

The volume of ejaculate ejaculate

free

OBESE

NONOBESE

OBESE

NONOBESE

was 69 -r IX.

in our laboratory.

As a group, the obese men we studied had less than two thirds the normal mean plasm levels of total testosterone, free testosterone, and FSH. Taken together, these findings represent a state of mild hypogonadotropic hypogonadism, which thus appears to be characteristic of obese men. Spermatogenesis,

Geometric l

mean:

95%

4.0-

C.L.

1.85 Ml

:

0.5-7.0

.

! i

- --t .

2.0-

/ o Nonokw (Nellon t Bunga)

.O

l

0

l.Ol

--f

l

l

-o.s-

I’

/

. . . .,... 5

PERCENTAQE

NONOBESE Fig.

3.

nonobese

Twenty-four-hour and obese

men.

mean

plasma

FSH

Ok80 Men (Thir Study)

in age-matched

Fig. obese

5. men.

20

40

, . , 60

a0

95

OF POPULATION WITH AN EQUAL LOWER EJACULATE VOLUME

Distribution

of

ejaculate

volumes

in

OR

nonobese

and

874

STRAIN ET AL.

Obese MenfThis Study) /

200 f

1

I

1’

loo: J /

/

/e

/

50

/ ./ /

t

25

PERCENTAGE OF POPULATION WITH AN EQUAL OR LOWER SPERM COUNT Fig. 6. men.

Distribution

of sperm counts in nonobese

and obese

libido, and potency were normal, which also qualifies the hypogonadism as relatively mild. The persistence of normal dihydrotestosterone levels in the face of decreased plasma levels of free and total testosterone is interesting, and implies that the relationship between these levels and the rate of DHT formation is more complex than a simple first-order reaction. Several previous authors have presented data suggestive of the presence of hypogonadotropic hypogonadism in obese men. Glass et a!.19 found normal levels of FSH and LH in these men. but commented that ‘6 . . . the absence of elevated gonadotropins . . . in these subjects with low free testosterone suggests . . . inappropriate suppression of their hypothalamic-pituitary axis.” Amatruda et a! reported in an abstract’ that “ . . . serum FSH was slightly reduced in two out of six morbidly obese patients” and concluded that “. . defect these data . . . suggest a possible hypothalamic to explain the depressed plasma testosterone”; in their subsequent full paper,” these workers reported normal FSH and LH levels but commented that “. . normal

LH concentration in the presence of significant decreases in total T and free T index . . . suggests . the hypothalamic-pituitary-gonada! axis was not responding appropriately to a low free T index.” Our data with respect to LH are similar, in that we found “inappropriately low” (though literally normal) values, but our findings with respect to FSH were much more definite: the values of the obese men as a group were displaced downwards, and the mean of the obese men was less than ?/3 the normal mean. It was this consistency of the subnormal FSH (we attribute the consistency to our measuring 24 hr mean plasma concentrations instead of “spot” concentrations) that led us to tie a!! the observations together into a picture of subclinical hypogonadotropic hypogonadism. The pathogenesis of this abnormality in obese men requires further investigation. We hypothesize that it results from partial suppression of the pituitary by the elevated plasma estrogen levels we’ and otherslm4 find in these men. Since these elevated levels, in turn, probably result from increased conversion of S4androstenedione to estrone,’ 4 it follows that suppression of adrenocortica! secretion of A4-androstenedione should lower them and thereby eliminate the hypogonadotropic hypogonadism. Preliminary studies in four patients in our laboratory” indicate that a 1 wk course of corticosteroids (which depressed plasma A’-androstenedione levels by about 55%) produced substantial normalization of the plasma estrone, estradio!, testosterone, and FSH levels. Though the results of these pilot studies require confirmation in a larger group of patients, they appear to support our hypothesis. ACKNOWLEDGMENT The authors gratefully

acknowledge

tance of Anne Thalassinos and Nathan noassay) and William Terri

Levis, Marc

Greenhut,

Reitman.

the expert

technical

assis-

Katz (hormone radioimmu-

Joan Greenhut,

Susan Silverman,

Guillemet

Barbet,

David Schessel. and

Marc Schessel (24 hr blood-sampling and NPT studies).

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MA,

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beim Mann

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12. Zumoff B, Rosenfeld RS, Strain GW, et al: Sex differences in the 24-hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults. J Clin Endocrinol Metab 51:330333.1980 13. Boyar RM, Rosenfeld RS, Kapen S, et al: Human puberty: Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest 54:609-618, 1974 14. Yates FE, Urquhart J: Control of plasma concentrations of adrenocortical hormones. Physiol Rev 42:359-443, 1962 IS. Rosner W: A simplified method for the quantitative determination of testosterone-estradiol-binding globulin activity in human plasma. J Clin Endocrinol Metab 34:983-988, 1972 16. Midgely AR: Radioimmunoassay for human follicle-stimulating hormone. J Clin Endocrinol Metab 27:295-299, 1967 17. Midgely AR: Radioimmunoassay: A method for human

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Bunge RG: Semen of male fertility

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20. Strain GW, Zumoff B, Levin J, et al: Reversal of hyperestrogenemia and hypogonadotropic hypogonadism in obese men by corticoid administration. Am J Clin Nutr 34:618. 1981 (Abstr) 21. Mall GW. Rosenfield RL: Testosterone binding and free plasma androgen concentrations under physiological conditions: Characterization by flow dialysis technique. J Clin Endocrinol Metab 49:730, 1979