SEMINAR REPORT

TOPIC:
THE INTERACTION OF THE REPRODUCTIVE AXIS
WITH ENERGY BALANCE

SUBMITTED BY:

EHI ASHLEY (Miss)

BMS1702212

DEPARTMENT OF PHYSIOLOGY
SCHOOL OF BASIC MEDICAL SCIENCES
UNIVERSITY OF BENIN, EDO STATE, NIGERIA

SUBMITTED TO:

PROF. AGOREYO F.O.

MAY, 2021.

i
 CERTIFICATION

This is to certify that this seminar work was carried out by EHI

ASHLEY, with the matriculation number BMS1702212 in partial fulfillment

for the award of Bachelor of Science Degree (B.Sc) in the Department of

Physiology, School of Basic Medical Sciences, College of Medical Science,

University of Benin, Benin City, Edo State.

____________________ ___ ____________________

PROF. AGOREYO F.O. DR. C.D. EKPRUKE
(Seminar Supervisor) (Seminar Co-ordinator)

____________________ ____________________
Date Date

ii
 DEDICATION

I dedicate this work to God almighty, for his mercies, infinite wisdom,

and love and also to my family for their love and unwavering support.

iii
 ACKNOWLEDGEMENTS

I would like to express my deep gratitude to my supervisor, Professor

Agoreyo for his invaluable guidance throughout this research. I am extremely

grateful to my parents for their love, prayers, care and sacrifices for educating

and preparing me for my future.

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 TABLE OF CONTENTS

• FIRST PAGE i

• CERTIFICATION ii

• DEDICATION iii

• ACKNOWLEDGEMENTS iv

• TABLE OF CONTENTS v

• ABSTRACT vi

1. Introduction 1

2. The Reproductive Axis 2

3. Energy Balance 4

I．Terms in energy balance 6

II．How much energy is stored in the human body? 6

III．Positive and negative energy balance 7

IV．Areas in the hypothalamus that control energy balance 7

4. Interaction of The Reproductive Axis With Energy Balance 9

I．Effects of Insulin, Leptin, Ghrelin, Kiss peptin 12-17

5. Conclusion 18

• REFERENCES 19-30
v
 ABSTRACT

Energy balance refers to the difference between the energy intake and the

energy output per day. A system is said to have a perfect energy balance if the

energy input equals the energy output. The reproductive axis is composed of the

hypothalamus, pituitary and gonads. It is commonly called the hypothalamo-

pituitary-gonad axis (HPG).

The HPG axis responds to changes in energy balances. Reproductive

functions which are controlled by the HPG axis require a lot of energy. For this

reason, it has been found that during periods of negative energy balance (such

as starvation, extreme exercise, pregnancy) that there is a rechanneling or

diversion of energy from reproduction to other processes so as to enable the

animal to survive. Alterations in energy homeostasis in conditions such as

cachexia and obesity have been linked to reproductive dysfunction in both

males and females.

The interaction between the HPG and energy balance is not well

understood. However, the HPG axis has been seen to respond to changes in

energy balance through the effects of some hormones and some other chemical

messengers. In the past, the proposed modulators of the reproductive axis were

the classical endocrine hormones, insulin, thyroid hormones, and the

glucocorticoids whose effects on metabolism are well established. However, in

the last 2 decades, other hormones from nonclassical endocrine tissues, such as

vi
the adipose and the gut, have gained momentum and are now recognized not

only as key metabolic regulators but also as relevant modulators of the

reproductive system (Fernandez-Fernandez et al., 2006; Hill et al., 2008; Tena-

Sempere,2007).

vii
 INTRODUCTION

Metabolism refers to the various processes in cells of organisms whereby

energy is released or produced from different foods we consume. It is divided

into anabolism (production of complex molecules from simpler ones) and

catabolism (the break down of complex molecules into simpler units as in

digestion).

Reproduction refers to a process whereby an organism generates new

organisms of the same kind. It is necessary for the perpetuation of a species and

the prevention of extinction of the species.

The reproductive axis controls reproduction and this is why impairment of the

reproductive axis can lead to infertility, sub-infertility and poor quality of

gametes. All levels of the reproductive axis also affect energy balance in one

way or the other. Reproduction and energy balance are very closely related and

this is why availability of energy is a major check point for successful

reproduction.

1
 THE REPRODUCTIVE AXIS

The reproductive axis consists of the hypothalamus, the pituitary (anterior

pituitary) and the gonads. Because of the close association of these structures in

reproduction, they are classified together as one system, the Hypothalamo-

Pituitary-Gonad (HPG) axis or system.

The hypothalamus here functions as the integration centre by receiving

various feedback stimuli and responding by secreting hormones that regulate the

function of the pituitary which in turn regulates the function of the gonads. The

hypothalamus controls the function of the pituitary via GnRH (gonadotropin

releasing hormone). The specific site from which GnRH is synthesized is the

preoptic area; the terminals of the neurons release the hormone at the median

eminence.

The hormone is released into the hypothalamohypophysial portal system

which conveys it to the anterior pituitary gland. GnRH regulates the release of

Leutenizing Hormone (LH) and Follicle Stimulating Hormone (FSH) which are

the gonadotropins. The release of GnRH occurs in a pulsatile fashion and this

causes the release of the pituitary hormones to also follow a pulsatile fashion.

LH and FSH regulate the reproductive functions of the gonads (gametogenesis

and steroidogenesis).

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LH stimulates the secretion of testosterone from the leydig cells of the

seminiferous tubules in males and in the females it stimulates ovulation and the

secretion of oestrogen and progesterone. FSH stimulates spermatogenesis (in

synergy with testosterone and growth hormone) and in females it stimulates

folliculogenesis (maturation of the follicle).

The release of the hormones in this axis is regulated by negative feedback

mechanism.

3
 ENERGY BALANCE

Energy balance refers to the difference between the total energy intake

and the total energy output per day. It is the difference between the total

amounts of calorie an individual takes in and the total amount of calories he/she

uses during the course of each day.

Energy is obtained from the foods and drinks we consume. The classes of

food that supply energy include

1. Carbohydrates: They are the primary source of energy in the diet. The

most preferred source of energy is in the form of glucose. Foods that contain

carbohydrates include bread, yam, rice, corn, millet, potatoes etc. The

amount of energy gotten from consuming 1 gram of glucose is 4kcal. (Hall

et al., 2012).

2. Proteins: These contain the same amount of energy as carbohydrates, 4kcal

but are not preferentially used for energy production. They are mainly used

for the repair of worn out tissues, replacement of dead cells, growth, and

other functions in the body. Only in conditions of carbohydrate deficiency

are the proteins used for production of energy (they are also used when they

are in excess in the diet). Foods that contain protein include meats (goat,

cow, sheep, fish, snake etc), milk, beans, bone etc.

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3. Fats: A gram of fat contains more calories than the combination of the

calories gotten from a gram of glucose and protein. However in spite of the

fact that they contain more amounts of energy (about 9kcal) than

carbohydrates (which have 4kcal), they are not preferred because they are

difficult to process. Examples of food that contain fats include meats (pork

meat), butter, cheese, oils, nuts etc.

Another source of energy is the alcohols. It is not advisable to use them

as source of energy as they are extremely difficult to break down, exerting stress

on the liver which also detoxifies them and at the end, they yield little amount

of energy.

The vitamins and minerals aid with metabolism and therefore affect energy

balance indirectly but are not direct sources of energy.

Small percentages of the food we consume become wastes and are

excreted (2-10%). The bulk of the foods are digested (oxidized) and absorbed

and are utilized by the cells for various processes such as growth, cell

maintenance, physical activity, pregnancy, lactation and other cellular

processes. The proportions of the food that are not used are stored in the body.

It should be noted that not all foods can be digested by the body and as such, not

all foods provide energy to the body.

5
Terms in Energy Balance

1. REE (Resting energy expenditure): The resting energy expenditure is the

amount of energy needed per day to stay alive if one does not perform any

form of exercise. It makes up about two-thirds of the energy need of the

body. (Hall et al., 2012) The REE ranges markedly from one person to the

other due mainly to the differences in body composition (fat versus muscle

of the body) and body size (the greater the body mass, the greater the REE

needed to stay alive). A great portion of the REE is due to the energy needs

of the Brain, Liver, Kidney and heart.

2. TEF (Thermic effect of food): This is the energy associated with the

processing and digestion of food. During digestion, large amount of energy

are released as heat. This causes a rise in temperature and is referred to as

the thermic effect of food. This effect is larger in proteins. (Hall et al., 2012)

3. AEE (Activity energy expenditure): This is energy due to structured

exercise and non-exercise movements (regular daily activity). (Hall et al.,

2012).

How Much Energy is Stored in the Human Body?

The average human can store as much as 130,000 kilocalories of fat,

primarily in the form of Triacylglycerol (TAGs). Hall et al., 2012 reported that

an average lean adult has about 35 billion adipocytes while an obese person has

6
about 140 billion adipocytes. (Hall et al., 2012) The body stores carbohydrates

in the form of glycogen stores. An average person can carry about 500g or

glycogen (about 350g in the muscles and 150g in the liver).

Positive Energy Balance

This occurs when a person takes in more energy than they can use up per

day or when a person’s energy input is greater than the energy output. This

leads to weight gain due to accumulation of left over carbohydrate, fat and

protein in the body.

Negative Energy Balance

This occurs when the energy intake is lesser than the energy output or

when a person takes a smaller amount of energy than he/she needs per day.

Negative energy balance can also be achieved by increasing the energy output

of the person mainly through exercise.

Areas in the Hypothalamus that Control Energy Balance

Energy balance is regulated by the hypothalamus a role referred to as the

vegetative function of the hypothalamus. The main site of energy control is the

arcuate nucleus. The arcuate nucleus contains neurons that control both satiety

(the proopiomelanocortin/cocaine- and amphetamine regulated transcript

{POMC/CART}- expression neurons) and hunger (the neuropptide related

7
protein {NPY/AgRP}- expressing neurons) (Baskin et al., 2000;Elias et al.,

1999).

Other hypothalamic areas involved in feeding control include the

periventricular nucleus, lateral hypothalamic nucleus (Elias et al., 1998).

8
 INTERACTION OF THE REPRODUCTIVE AXIS AND ENERGY

BALANCE

The interaction between the reproductive axis and energy balance is a

complex one. Several research studies have gone into understanding this

interaction and the molecules, pathways, and other factors involved. Yet there is

still more to be uncovered about this interaction.

Based on studies carried out on rodents (Kenedy, 1969) and human subjects

(Frisch, 1994; Frisch, 1997) it has been thought that female’s fat reserves must

exceed a particular level before ovulation can occur. However, it has now been

discovered with clarity that the current energy balance determines how the body

allocates energy and that energy is not allocated based on the total amount of

stored fat in the adipose tissues.

Irrespective of the cause of the negative energy balance, be it inadequate

food intake, or excessive locomotor activity etc, ovulation is suppressed in a

mammal. Similarly, ovulation occurs in mice whenever the current energy

balance permits except if the ovulation is blocked by non-metabolic stress,

social cues, or predictive seasonal cue such as photoperiod. Mice in the wild

continue to ovulate and become pregnant even though their current energy

reserves are not sufficient to carry their litter to term (Broson, 1985). In humans,

menstrual abnormalities, amenorrhea, and infertility can result from inadequate

food intake to compensate for energy demands; for instance when a severe

9
athletic training schedule is relaxed, LH pulses and menstrual cycle resume

without a significant increase in body fat content (Abraham et al., 1982;

DeFazio, 2002). The sensitivity of the reproductive axis to the current energy

availability can produce clinically recognised menstrual disturbances (De

Sausa, 2007).

NPY (Neuropeptide Y) Fibres Link Energy Balance and Reproduction

Within the Hypothalamus

These fibres have close associations with the cell bodies and dendrites of

GnRH neurons in the medial preoptic area. (Guy and Pelletier, 1988). Also the

NPY fibres in the median eminence may also act on the GNRH terminals

(Sabatino et al, 1987). Negative energy balance stimulates an increase in NPY

release from the paraventricular and preoptic areas. This in turn causes two

effects; an increase in feeding and a decrease in the release of GnRH. The

decrease in GnRH will in turn cause a decrease in release of LH and FSH and

consequently, a decreased activity of the gonads. In support of this hypothesis

made by hill et al, a suppression of basal LH levels by fasting fails to occur in

the NPY knockout female (Hill and Levine, 2003) and also ob/ob mice (mice

lacking leptin) that are also NPY deficient display improved fertility compared

with ob/ob controls (Erickson et al., 1996).

However, pharmacological findings in rats (Crowley and Kalra, 1987),

rabbits (Khorram et al., 1987), and monkeys (Woller, 1992) provides a

10
compelling case for the existence of two mechanisms, one inhibitory and one

stimulatory, through which endogenous NPY regulates the GnRH pulse

generator. In many species, there is an inverse relationship between NPY

release and GnRH levels, pulse amplitude, and pulse frequency in an

environment of low estradiol and progesterone, such as in unprimed,

ovariectomized animals (Allen et al., 1989). In these animals, steroid

replacement switches the effect of NPY to a robust positive one (Berria et al.,

1991;Titolo et al., 2006). Thus, surprisingly, NPY appears to be required for

GnRH surge production; LH surges are attenuated after NPY

immunoneutralization or Y1 receptor blockade on the day of proestrus (Guy and

Pelletier, 1988; Kalra and Crowley, 1992) .

Insulin as a Link Between Reproduction and Energy Balance

Insulin is a polypeptide released by the beta cells of the pancreas. It is the

only anti-diabetic hormone released in the body. It was found that neuron-

specific deletion of the insulin receptor (NIRKO mice) was found to lead to

increased body fat deposition and hypothalamic hypogonadism (infertility due

to reduced GnRH release) (Bruning et al., 2000). This confirms a role for

insulin in the control of reproduction. Intially, this role for insulin was based on

the proportionality between insulin levels and body adipose content (woods and

Porte). It has not been confirmed in vivo whether GnRH neurons express insulin

receptors. Because of this, scientist do not know whether the actions of insulin

11
in this setting are mediated by the direct action of insulin on the GnRH neurons

or by altering input from secondary insulin sensitive neurons.

Insulin receptors are expressed in the medial portion of the arcuate

nucleus where NPY/AgRP-expressing neurons are located (Baskin et al., 1997).

Indeed, insulin affects the expression of NPY; in fasted animals,

intracerebroventricular (icv) administration of insulin decreases NPY mRNA in

the arcuate nucleus and NPY peptide in the paraventricular nucleus of the

hypothalamus (Schwartz et al., 1991; Wand and Leibowitz, 1997). Insulin-

deficient diabetic rats show increased hypothalamic levels of both NPY and its

mRNA that are normalized by systemic insulin therapy (Abe et al., 1991;

Schwartz et al., 1992). High numbers of insulin receptors are also found on

POMC/CART neurons (Benoit et al., 2002) (9). Interestingly, no obvious

metabolic or reproductive phenotype was seen in mice lacking insulin receptors

only in POMC neurons (Konner et al., 2007) (59).

Leptin as a Link Between Reproduction and Energy Balance

Also referred to as the ‘satiety hormone’, it is secreted by the white

adipose tissue in proportion to the current body stores of energy.

Several studies have proved that leptin serves as a link between the magnitude

of body fat stores and different neuroendocrine axis (Fernandez-Fernandez et

al., 2006; Casanueva and Dieguez, 1999; Tena-Sempere, 2007; Ahima, 2000).

12
 Leptin plays a key role in the metabolic control of puberty and fertility

(Fernandez-Fernandez et al., 2006; Casanueva and Dieguez, 1999; Tena-

Sempere, 2007; Ahima, 2000; Cheung et al., 21997). This was based on the

observation that in both humans and mice that lacked leptin action, puberty was

delayed or even absent and fertility was disturbed (Roa et al., 2010). Absence of

leptin (ob/ob mice) or leptin receptor (db/db mice) results in hyperphagic

morbid obesity and insulin resistant diabetes (Coleman, 1978) in both humans

and mice. The fasting induced suppression of LH secretion and fertility can be

blocked by leptin administration (Gonzalez et al., 1999; Kohsaka et al., 1999;

Negatani et al., 1998; Negatani et al., 2000).

In women with amenorrhea (exercise or anorexia-induced), leptin

treatment raises pulse frequency and levels of LH, ovarian volume, number of

dominant follicles, and estradiol levels (Licinio et al., 1998; Welt, 2004).

Furthermore, ob/ob mice have low LH levels and are infertile, and leptin

administration, but not weight loss alone, restores their fertility (Barash et al.,

1996; Chehab et al., 1996; Mounzih et al., 1997; Ziotopoulou et al., 2000).

Expression of leptin receptor (LepR) in the brain of db/db mice or mice

otherwise null for LepRs restores fertility completely in males and partially in

females (de Luca et al., 2005; Kowalski et al., 2001).

The above studies depict a role for leptin in control of GnRH release.

However, it has been discovered that GnRH neurons do not express leptin

receptors under normal conditions. (Burcelin et al., 2003; Finn et al., 1998;

13
Hakansson et al., 1998). Instead, leptin is believed to act indirectly via

interneurons impinging on GnRH-secreting cells in the hypothalamus

(Cunningham et al., 1999; Thornton et al., 1997), although the identity of such

interneurons is unclear.

Evidence is growing that leptin has important targets aside from those in

the arcuate nucleus (Grill et al., 2002; Huo et al., 2007). Leptin receptor is

found in other hypothalamic nuclei, including the dorsomedial subdivision of

the ventromedial nucleus (VMH), the caudal subdivision of the dorsomedial

nucleus (DMH), the premammillary ventral nucleus (PMV), and, in a small

extension, in the paraventricular nucleus (Elmquist et al., 1998; Fei et al., 1997;

Mercer et al., 196) (34, 36, 65). Indeed, neurons expressing Leptin receptor in

the VMH also respond to glucose and insulin (Canabal et al., 2007) (15), but the

pathways downstream of VMH neurons responsive to metabolic signals are not

yet identified. In addition, the DMH and the PMV strongly innervate areas

related to reproductive control, including the anteroventral periventricular

nucleus (AVPV) and the medial preoptic area (Canteras et al., 1992., Rondini et

al., 2004; Thompson et al., 1996; Thompson et al., 1998). However, whether

these projections originate from neurons responsive to leptin and are

physiologically relevant to leptin action in reproductive control remains

unsettled.

14
 Curiously enough, direct gonadal effects of leptin appear to be

predominantly inhibitory (Caprio et al., 200; Tena-Sempere and Barreiro, 2002;

Tena-Sempere et al., 1999); the paradoxical suppression of gonadal function in

conditions of severe hyperleptinemia may help to explain the clinical

observation that morbid obese men frequently display low testosterone levels

and hypogonadism (Caprio et al., 2001).

One should keep in mind that although threshold leptin levels are

required to achieve normal pubertal development and to maintain reproductive

function in adulthood, yet, leptin alone is not sufficient to evoke the whole set of

activatory events leading to puberty onset. In fact, whereas the circulating levels

of leptin rise during the pubertal transition in girls (Garcia-Mayor et al., 1997),

puberty onset in boys and male monkeys does not apparently require a similar

increase in leptin levels (Garcia-Mayor et al., 1997; Plant and Durrant, 1997).

For this reason the precise role of leptin in males is not completely known.

Ghrelin as a Link Between Reproduction and Energy Balance

Ghrelin generally stimulates food intake (Cummings and Overduin,

2007). Ghrelin also modulates glucose homeostasis and the secretion of insulin

by the pancreas (Van der Lely et al., 2004; Sun et al., 2003), and it conducts

central regulatory effect on energy expenditure and nutritient partitioning.

Ghrelin also acts in concert with other important metabolic signals such as

leptin in the modulation of energy homeostasis (Zigman and Elmquist, 2003).

15
 The action of ghrelin are considered to be opposite of that of leptin.

Whereas the circulating levels of leptin is proprtional to the amount of white

adipose tissue, the levels of ghrelin are negatively correlated with the body mass

index (BMI); hence ghrelin is thought to act as a long-term signal for energy

insufficiency. This menas that the levels of ghrelin increses during conditioms

of negative energy balance. It has been reported that ghrelin inhibits the onset of

puberty by suppressing the release of gonadotropins (Tena-Sempere, 2008;

Tena-Sempere, 2008; Fernandez-Fernandez et al., 2005; Martini et al., 2006).

Male rodents were found to be more responsive to the effects of ghrelin as

opposed to leptin in which the female rodents were the ones that were more

responsive (Fernandez-Fernandez et al., 2006). Whether puberty in humans is

sensitized to the effect of ghrelin is not clarified. However, hormonal studies

have reported a progressive reduction in the circulating levels of ghrelin during

the course of puberty in humans (Soriano-Guillen et al., 2004) which describes

a permissive role of ghrelin for puberty. Ghrelin seems to act as an inhibitory

signal for the gonadotropic system in adulthood. Thus, intracerebral and

systemic administration of ghrelin can induce marked inhibitory responses in

terms of LH, and to a lesser extent FSH release in different species. This

capacity of ghrelin to inhibit GnRH release has be recorded in many species

including sheep, non-human primates, and even humans. Ghrelin was found to

reduce the release of the gonadotropins and sex steriods in several animals and

in humans (Fernandez-Fernandez et al., 2005; Martini et al., 2006; Fernandez-

16
Fernandez et al., 2006; Furuta et al., 200; Fernandez-Fernandez et al., 2994;

Vulliemoz et al., 2004; Iqbal et al., 2006; Kluge et al., 2007; Fang et al., 2012;

Sirotkin et al., 2008; Moshtaghi-Kashanian and Razavi, 2009).

Kiss Peptin

Kisspeptin, the product of KISS1 gene, are the gatekeepers of

reproduction that centrally work upstream GnRH secreting neurons thus

conveying on HPG axis sex steroid feedbacks and environmental cues,

including information of nutritional status. Apart from linking neuronal

pathways involved in the control of energy balance and reproduction,

kisspeptins peripherally exert modulatory activities on different tissues like

adipose tissue and gonads (Chianese et al., 2016; Pinilla et al., 2012).

17
CONCLUSION

A better understanding of the neural circuitry underlying leptin signalling

in the hypothalamus is critical not only for the advancement of our knowledge

of the connection between metabolism and reproduction but also for future

development of treatment strategies for hypothalamic hypogonadism.

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