Obesity and reproduction
George A.Bray
Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA
Obesity produces a variety of alterations in the
reproductive system and, similarly, manipulations of the hypothalamic-pituitary-gonadal
axis produce changes in food intake, body weight
and fat distribution. In men, the primary effects
of obesity are a weight related reduction in
testosterone and, with massive overweight, a
reduction in free testosterone. In females, the
weight-related development of menarche leads
to earlier menarche in obese girls than in normal
weight girls. One explanation for the relationship of fatness to menarche may be the ob
protein (leptin) which is defective in the obese
ipb/ob) mouse. Leptin is secreted by adipose
tissue in proportion to the quantity of fat and
may serve as a signal to the hypothalamus that
fat stores are adequate to nourish a conceptus
to term. In women, parity affects obesity and
obesity in turn affects the regularity of the
menstrual cycle. In many experimental animals
with obesity, particularly the genetic forms of
obesity, there is complete infertility in the
females and marked impairment of reproductive function in the males. In animals with
hypothalamic lesions, there is a gender effect
on the magnitude of weight gain associated with
the sexually dimorphic regions in the medial
preoptic area. Castration with removal of
oestrogen is followed by obesity in female
animals and this can be prevented, as can
most forms of obesity, by adrenalectomy. The
inhibitory effects of oestrogen on food intake
may result from suppression of neuropeptide-Y
or galanin peptidergic systems in the arcuate
nucleus or medial preoptic area.
26
Key words: body fat/galanin/neuropeptide Y/neurotransmitters/steroids
Introduction
Both over-nutrition and under-nutrition are associated with alterations in the reproductive system.
In women who are long-distance runners, ballet
dancers, or those who undergo significant weight
loss from anorexia nervosa, the menstrual cycle
becomes irregular or ceases. At the other extreme,
excess body weight and obesity are associated with
alterations in the reproductive system in women
and frequently accompany obesity in experimental
animals. This paper will focus primarily on the
relationship between obesity and reproduction and
will be divided into two parts, the first part dealing
with alterations in human beings, and the second
part with data from experimental animals which
may provide enhanced understanding of the altered
state in human beings.
Obesity and the reproductive system in
human beings
Males
Table I presents a brief summary of the alterations
observed in males in relation to obesity. Although
testicular size remains normal, the plasma concentration of testosterone decreases as obesity
increases (Kley et al, 1980). This decrease in total
testosterone results from a reduction in the level
of sex hormone binding globulin (SHBG). The
reduction in SHBG, on the other hand, appears to
reflect the increased level of insulin and insulin
© European Society for Human Reproduction & Embryology
Human Reproduction Volume 12 Supplement 1 1997
Obesity and reproduction
Table II. Ovary and obesity
Table I. Testis and obesity
Testis size
Serum testosterone (total)
(free)
SHBG
Production testosterone
FSH-LH (basal)
Response to LHRH
Clomiphene
HCG stimulation
Oestrone and oestradiol production
N
I
N
i
N
N
N
N
N
T
Ovary
T hyalinization and atretic
follicles
SHBG
i
Oestadiol turnover
I
Androstenedione —> oestronet
DHEA production
T
Urinary 17-KS
T
LH + FSH-basal
N
Response to LHRH
N
nrr rrlz-ikniin- TYHF A —
SHBG = sex hormone binding globulin; FSH = follicle
stimulating hormone; LH = luteinizing hormone; LHRH
luteinizing hormone-releasing hormone; HCG = human
chorionic gonadotrophin.
dihydroepiandrosterone; KS = ketosteroids; LH = luteinizing
hormone; FSH = follicle stimulating hormone; LHRH =
luteinizing hormone-releasing hormone.
resistance (Haffner et al, 1990, 1991, 1992), and
SHBG has been used as a surrogate for increased
risk related to obesity and insulin resistance
(Zumoff et al, 1990; Pasquali et al, 1995). The
level of free testosterone in contrast to total testosterone is normal in men of normal weight or
moderate obesity but with massive obesity there
may also be a decrease in free testosterone as well
(Zumoff et al., 1990). In men, there is a weight
related rise in both oestradiol and oestrone concentrations. In contrast to the changes in testosterone
and SHBG, the pituitary gonadotrophins remain
normal. Similarly, the pituitary release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) are normal following injection of
gonadotrophin-releasing hormone (GnRH).
process. According to this hypothesis the growth
spurt begins at a body weight of ~31 kg. The
maximal rate of weight gain occurs at 39 kg and
menstruation begins when the body weight reaches
48 kg or contains ~22% body fat. Because obese
girls grow faster and enter this critical weight
range at a younger age, menses on average usually
occur a year earlier. When fat loss occurs and drops
below this critical range, menstruation frequently
disappears as observed in ballet dancers and
distance runners.
The recently isolated ob-protein (leptin) may
provide this signal. This protein is only produced
in adipocytes. The larger the fat mass the more
leptin that is produced. When this protein is defective in the obese (ob/ob) mouse, the reproductive
system remains pre-pubertal. Leptin provides an
ideal signal to tell the brain that the body has
sufficient stores of nutrients to nourish the fetus
to term.
Women with hirsutism and anovulatory cycles
are on average 14 kg heavier than women with no
menstrual abnormalities. As the degree of excess
weight increased the number of women with anovulatory cycles also increased. Of women who were
<20% overweight only 2.6% had anovulatory
cycles compared with 8.4% of women who were
>74% overweight. The greater the duration of
obesity the greater the amount of facial hair which
is present. Obesity occurring in the teenage years
is associated with an increased number of married
women who never became pregnant and with a
higher likelihood of surgery for polycystic ovaries.
Females
Because of the complexity and cyclicity of the
female reproductive system, the relationship with
obesity is more complicated than in men. These
changes are summarized briefly in Table II. In
contrast to the normality of the testes in obese men,
there is an increased number of atretic follicles and
increased ovarian hyalinization in obese women.
The onset of menarche may occur at a younger
age in obese girls than in normal weight girls. One
explanation for this phenomenon was proposed by
Frisch and Revelle (1971). It is based on the
observation that menstruation is initiated when
body weight reaches a 'critical mass'. As the
growth rate accelerates in late childhood, the percentage of fat rises and initiates the pubertal
27
G.A.Bray
These findings indicate that excess body weight
can influence the age at onset of menstruation as
well as the subsequent regularity of this process.
Though the mechanisms for the disorders are
unknown the attendant hormonal abnormalities in
obese women are reversible with weight loss.
The function of the reproductive system in
women is complicated by the metabolism of steroids in other organs with resulting production of
biologically active steroidal products. A4-Androstenedione which is produced by the adrenal gland
can be converted to oestrone by the stromal cells
of adipose tissue. Muscle may also convert oestrone
to oestradiol. Because the ovarian production of
oestradiol in premenopausal women is high, the
enhanced conversion of A4-androstenedione to
oestrone in obese women does not increase circulating concentrations of oestrogen. However, in the
post-menopausal woman, the concentrations of
oestrogen appear to increase. When castrated obese
and non-obese women were given implants of
oestradiol, the obese women had higher levels of
A4-androstenedione and free testosterone. Studies
of oestradiol metabolism show that obese women
had decreased hydroxylation at the C2 position
and increased oxidation at the 17-oc position.
Hydroxylation of the 16-oc position, however, was
not significantly influenced by obesity.
Pregnancy influences obesity and vice versa.
Obese women tend to have heavier infants and
larger placentas. Both placental weight and maternal weight are predictors of childhood weight
at entry to school. Conversely, the number of
pregnancies influences the degree of obesity.
Women who have children have a step-wise
increase in weight and likewise show an increased
prevalence of obesity.
Just as the onset of menarche is earlier in obese
women, so data suggests that the onset of ovarian
failure and increased production of FSH at menopause occurs four years earlier in obese women
than in women of normal weight. In women there
is a positive association between the degree of
visceral fat accumulation and free testosterone
levels. The increased testosterone produced from
peripheral tissues may account for enhancing visceral fat accumulation in post-menopausal women.
28
The polycystic ovary syndrome (PCOS)
Obesity, hirsutism, anovulation, multiple cysts
in the ovaries and insulin resistance characterize a
syndrome known as the polycystic ovarian syndrome (PCOS), a disorder of unknown aetiology
(Kiddy etal., 1990; McClusky etal., 1992;Pasquali
and Casimirri, 1993; Insler et al., 1993; Holte et al.,
1994; Singh et al, 1994). The high frequency of
increased fat tissue in such women again suggests
the coupling of reproduction to nutritional factors.
This syndrome is characterized by increased levels
of circulating LH which is secreted in exaggerated
pulses. The increased LH is thought to be responsible for the increased ovarian production of steroids
and impaired follicular development. When LH
secretion is inhibited with long-acting GnRH agonists, androgen secretion is reduced showing the
importance of LH stimulation of the ovary in the
hyperandrogenization associated with this state.
In contrast to the increased levels of LH, FSH
concentrations are generally reduced (Dunaif etal.,
1989; Nestler et al, 1991; Rittmaster, 1993; Buyalos et al, 1995; Dos Ries et a/., 1995). Women
with PCOS and anovulation have high levels of
insulin resistance and altered IGF-I binding protein
levels. It may enhance risk for myocardial infarction (Dahlgren et al, 1992; Anderson et al, 1995)
and can be treated with antiandrogens (DiamantiKanarakis et al, 1995).
Experimental obesity and the reproductive
system
Hypothalamic obesity
In early studies following the demonstration by
Hetherington and Ranson (1940) that electric
lesions in the ventromedial hypothalamus (VMH)
could induce hyperphagia and obesity, Brobeck
et al. (1942) demonstrated that these lesions not
only induced hyperphagia and increased body
weight but also decreased physical activity and
produced irregular oestrous cycles. Subsequent
studies demonstrated that VMH lesions were produced more routinely in female rats which have
increased numbers of sexually dimorphic neurons
in the ventromedial and preoptic areas. As hypothalamic lesions became more discrete, two separable syndromes emerged, neither of which impaired
Obesity and reproduction
Table III. Models of obesity
Animal model
Chromosome
Gene defect
Protein
Reproductive
status
Mechanism
Dominant
Yellow mouse (Ay/a)
2
Agouti
overexpressed
133/A
Impaired
Competes with
MSH receptors
Recessive
Obese (ob/ob) mouse
6
164
Infertile
?Receptor
for ob
Infertile
9
Infertile
Signal from feet
to brain about
nutrition
Receptor for
ob protein
May be identical
to db
Peptides
not cleaved
Diabetes (db/db) mouse
4
Stop codon
105 produces
truncated product
?
Fatty rat (fa/fa) mouse
5 (mouse 4)
?
Fat (Fat/Fat) mouse
8
Carboxy
peptidase E
Tub (Tub/Tub) mouse
7
Polygenic/diet induced
AKR-mouse/OM rat
KK mouse
New Zealand Obese mouse
Psammomys Obesus - Sand rat
Tuco loco
the reproductive axis (Bray et al., 1989). The
first syndrome associated with discrete lesions
in the ventromedial nucleus was associated with
decreased activity of the sympathetic nervous
system, increased activity of the parasympathetic
nervous system and little or no increase in food
intake. A second syndrome associated with discrete
lesions in the paraventricular nucleus was associated with hyperphagia but with limited alterations
in the function of the autonomic nervous system.
These two discrete areas suggest that obesity
can be the result of hyperphagia alone following
damage to the paraventricular nucleus or occur in
relation to disturbances in the balance between
sympathetic and parasympathetic nervous systems
observed after lesions in the ventral medial nucleus,
(VMN) or reciprocal changes in these systems
observed after lesions in the lateral hypothalamus.
Genetic obesity
Table III is a list of the single gene models of
obesity and the status of their reproductive system.
In the obese (ob/ob) and diabetes (db/db) mouse,
the females are infertile and the males show marked
impairment in their reproductive function. The
fatty Zucker rat (fa/fa), which has a syntonic
Impaired
?
Impaired
genetic locus on rat chromosome 5 to the diabetes
(db/db) mouse locus on chromosome 4, also shows
marked impairment of the fertility of the female
and some impairment of mating in the male. Other
models, including the fat mouse, tubby mouse and
the yellow mouse show only modest impairments
in fertility relative to the recessively inherited
forms described above. Removal of adrenal steroids
by adrenalectomy or treatment with RU486 will
reduce weight gain and correct most of the abnormalities in the recessively inherited forms of
obesity. The two systems for which adrenalectomy
produces no improvement are the reproductive
system and the temperature regulatory system
(Shimizu et al, 1993). In this paper, we suggest
that these defects might modulate the action of a
number of members in the steroid super family
including glucocorticoid, oestradiol, aldosterone,
thyroxine, vitamin D and retinoids.
Recently, the genes and gene products for three
of these mice have been identified. The agouti
protein in the yellow mouse is over-expressed in
a variety of tissues and appears to be a competitive
inhibitor for the melanocyte stimulating hormone
(MSH) receptor (Lu et al., 1994). Such an inhibition would impair the darkening of the coat colour
29
CA.Bray
by blocking the response to MSH and would lead
to hyperphagia by blocking the inhibitory effects
of feeding observed with oc-MSH. The second gene
to be cloned was the ob gene on chromosome 6
(Zhang et al, 1994). In the obese (ob/ob) mouse,
this 167 amino acid protein is truncated with a
stop codon at bases 105 in the protein sequence
leading to a truncated ineffective protein. The
message for this gene is expressed only in white
adipose tissue. This suggests that this secreted
peptide may be the regulator between adipose
tissue and the brain, muscle, and liver, which has
been long sought. This peptide could provide the
signal for the onset of menarche since the quantity
of ob protein appears to be related to the quantity
of body fat (Considine et al, 1995). The third
mouse, FAT, has a defective carboxypeptidase
which is involved in cleavage of a number of
peptides.
Oestrogen and obesity
In experimental female animals, castration produces obesity (Wade and Schneider, 1992). This
effect can be prevented by treatment with oestradiol. Rhythm in the reproductive cycle is also
associated with alterations in food intake, with
oestrogen producing a decrease in food intake in
rodent models. Like the genetic forms of obesity,
adrenalectomy prevents the effects of castration
on the development of obesity (Bray et al., 1989).
Neuropeptides, reproduction and food intake
The isolation of neuropeptide Y (NPY) in 1982
(Tatemoto et al., 1982) and galanin in 1983
(Tatemoto et al., 1983) opened a new vista on the
relation of food intake and reproduction. NPY
was rapidly recognized to increase food intake
dramatically when injected into the ventricular
system of the brain or into many hypothalamic
nuclei. Food intake was particularly increased
during the nocturnal phase. If NPY was chronically
infused, obesity could be produced (Cazeflis et al.,
1993). Antibodies to NPY (Shibasaki et al, 1993)
or antisense oligonucleotides to NPY injected into
the paraventriculer nucleus (PVN) (Akabayashi
et al, 1994) both decreased food intake. Injections
of NPY produced a drastic suppression of ejaculatory and mounting behaviour in experimental
30
animals. Castration in males was shown to decrease
the mRNA concentration for NPY in the arcuate
nucleus and testosterone restored this value to
normal (Sahu et al, 1992; Urban et al, 1993).
Progesterone was shown to produce a parallel
modulation in the concentration of GnRH and
NPY. Sar et al. (1990) and Brann et al. (1991)
showed that oestradiol and NPY were co-localized
in a subset of cells in the arcuate nucleus. The
clear reciprocal relationships between feeding and
the reproductive system were demonstrated in the
work of Catzflis et al. (1993) who infused NPY at
several dose levels into the ventricular system of
rats. There was a dose-dependent increase in food
intake, water intake and body weight in these
animals. Similarly there was a dose-dependent
decrease in pituitary and ovarian weight and a
significant inverse correlation between ovarian and
pituitary weight and food intake suggesting that
NPY had activated one system and inhibited
another.
Galanin likewise has important effects on feeding and on the reproductive system. Injection of
galanin into the ventricular system or into the
paraventricular nucleus significantly increases food
intake and inhibits the sympathetic nervous system.
Unlike NPY, however, chronic infusion of galanin
does not produce a chronic weight gain or obesity
(Smith et al, 1994). Galanin will increase the
intake of fat or carbohydrate depending upon the
primary preference of the animal. Use of antisense
oligonucleotides to galanin mRNA produced a
dramatic decline in fat ingestion and body weight
in rats suggesting that this peptide may be important
in the control of feeding. Galanin-like immunoreactivity is increased in the median eminence and
anterior pituitary during the first oestrous and
dioestrous phases of the reproductive cycle. Injection of pregnant mare's serum gonadotrophin
(PMSG) increased mRNA for galanin by approximately two-fold in the paraventricular and preoptic
regions of the hypothalamus (Gabriel et al, 1992).
In the medial preoptic area (MPOA), 13% of the
cells which concentrate oestradiol were positive
for immunoreactive galanin. There was likewise an
increase of 3-5 fold in the oestradiol concentrating
cells in the sexually dimorphic medial preoptic
areas of female versus male rats.
Obesity and reproduction
These data on galanin and NPY show that each
has an important role in the reproductive process
modulating the LH surge and GnRH production
by hypothalamic neurons. Can either of these
peptides directly account for the castration induced
hyperphagia and obesity? The gonadal hormones
appear to increase galanin and NPY and yet
decrease food intake. One possibility is suggested
by the interaction between progestogens and the
reproductive system. The progestogen megestrol
acetate (Megace) is known to increase food intake
and body fatness and has been used in treatment
of patients with breast cancer. In experimental
animals, Megace increased food intake and
increases the concentration of NPY in the arcuate
nucleus, lateral hypothalamus, MPOA, VMN and
+ DMN (McCarthy et al, 1994). One might argue
that the feeding system has a reciprocal relationship
to arcuate NPY neurons modulating feeding which
involve the progestational receptors serving a positive effect and the oestradiol receptors serving as
an inhibitory system to the progestational agent.
Such a two pronged system could account for the
effects observed in the hyperphagia and obesity
associated with castration and the suppression of
food intake associated with oestrogen and its
stimulation by progestational agents.
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