ROLE OF HYPOTHALAMIC-PITUITARY-GONADAL AXIS IN

SPERMATOGENESIS
SEMINAR

BY
BADMUS BALIQIS DAMILOLA
ANA/20/2546

SUPERVISED BY
MR OLUWATUNASE GIDEON

SUBMITTED TO

DEPARTMENT OF ANATOMY,

FACULTY OF BASIC MEDICAL SCIENCES,

UNIVERSITY OF MEDICAL SCIENCES, ONDO, ONDO STATE.

IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR

THE AWARD OF BACHELOR OF SCIENCES (B.Sc.) DEGREE

IN ANATOMY

AUGUST, 2024

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 CERTIFICATION

This is to certify that this report was written by Badmus Baliqis Damilola with

matriculation number ANA/20/2546 under the supervision of Mr Oluwatunase

Gideon and submitted to the Department of Anatomy, Faculty of Basic Medical

Sciences, University of Medical Sciences, Ondo, Ondo State in partial fulfillment

of the requirements for the award of Bachelor of sciences (B.Sc.) degree in

Anatomy.

Badmus Baliqis Damilola ____________________

Student Signature/Date

Mr Oluwatunase Gideon ____________________

Seminar supervisor Signature/Date

Dr. Kingsley Iteire ____________________

Head of Department Signature/Date

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 DEDICATION

This report is dedicated to God and to my loving parents, siblings and friends who

have always supported me.

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 ACKNOWLEDGEMENT

I acknowledge almighty Allah, for His divine grace and favor. My profound

gratitude goes to my seminar supervisor, Mr Oluwatunase Gideon for his

assistance and support towards the successful completion of this seminar report. I

also wish to express my gratitude to my parents, Mr and Mrs Badmus for all their

efforts and assistance.

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 TABLE OF CONTENTS

CERTIFICATION………………………………………………………………...2

DEDICATION………………………………………………………………….....3

ACKNOWLEDGEMENT………………………………………………………....4

TABLE OF CONTENTS…………………………………………………………..5

CHAPTER ONE…………………………………………………………………...8

INTRODUCTION…………………………………………………………………8

1.1 GROSS ANATOMY OF THE HYPOTHALAMUS………………………….8

1.1.1 EMBRYOLOGY…………………………………………………………...12

1.2 ANATOMY OF THE PITUITARY GLAND………………………………...12

1.3 GROSS ANATOMY OF THE TESTES……………………………………...15

1.3.1 HISTOLOGY OF THE TESTES…………………………………………..17

1.3.2 EMBRYOLOGY…………………………………………………………...18

1.4 SPERMATOGENESIS……………………………………………………….19

CHAPTER TWO…………………………………………………………………22

2.1 ANATOMY OF THE HPG AXIS……………………………………………22

2.2 HYPOTHALAMO-HYPOPHYSEAL PORTAL SYSTEM…………………23

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2.2.1 VESSELS INVOLVED IN THE HYPOTHALAMO-HYPOPHYSEAL

PORTAL SYSTEM……………………………………………………………24

2.3 HORMONAL COMMUNICATION OF THE HPG AXIS……………….25

2.4 NEURONAL COMMUNICATION OF THE HPG AXIS………………..26

CHAPTER THREE……………………………………………………………28

3.1 REGULATION OF SPERMATOGENESIS BY HPG AXIS………..........28

3.2 EFFECTS OF HYPOTHALAMIC HORMONES ON THE ANTERIOR

PITUITARY AND TESTES……………………………………………………29

3.2.1 EFFECTS OF GONADOTROPIN ON THE GONAD (TESTES)………30

CHAPTER FOUR………………………………………………………………33

4.1 DISORDERS ASSOCIATED WITH THE HPG AXIS…………………….33

4.1.1 MALE HYPOGONADISM……………………………………………….33

4.1.2 DELAYED PUBERTY IN MALES………………………………………35

4.1.3 HYPERPROLACTINEMIA IN MALES…………………………………37

4.1.4 KALLMANN SYNDROME IN MALES………………………………...38

CHAPTER FIVE………………………………………………………………..40

CONCLUSION………………………………………………………………….40
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REFERENCES……………………………………………………………………43

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 CHAPTER ONE

1.0 Introduction

Spermatogenesis is the process by which mature spermatozoa are produced from

spermatogonia stem cells in the testes. This process is critical and significance for
male fertility and the continuation of genetic material across generations. This
intricate process is tightly regulated by a complex interplay of hormonal signals,
primarily governed by the hypothalamic-pituitary-gonadal axis.

The HPG axis, which involves the coordinated actions of the hypothalamus,
pituitary gland and gonads, orchestrates the production and release of key
hormones that drive spermatogenesis. Understanding the mechanisms by which the
HPG axis influences spermatogenesis is crucial for advancing our knowledge of
male reproductive health and addressing issues related to infertility.

This seminar work aims to elucidate the critical role of the HPG axis in the
regulation of spermatogenesis.

1.1 Gross Anatomy of the Hypothalamus

Hypothalamus is an integral part of the brain. It is a small cone shaped structure

that projects downward from the brain. It extends from the lamina terminalis
anteriorly, to the tegmentum of the midbrain posteriorly. Its superior border is
marked by the hypothalamic sulcus, a shallow groove which separates it from the
thalamus. Its inferior surface bears the optic chiasm anteriorly, the tuber cinereum
centrally and the mammillary bodies posteriorly. The inferior aspect of the third
ventricle forms the medial border of the hypothalamus while the lateral border is
formed by the substantia innominate rostrally and the posterior limb of the internal
capsule caudally (Swanson, 2000).

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Fig. 1 Anatomy of the hypothalamus (Roberto et al., 2023)

Hypothalamus can be divided in the coronal plane from medial to lateral into three
zones:

 Periventricular zone
 Intermediate (medial) zone
 Lateral zone (Moore et al., 2018).

Based on proximity to the optic chiasm, tuber cinereum and mammillary bodies,
hypothalamus can be further divided into four areas:

 Preoptic
 Anterior hypothalamic(supraoptic)region
 Tuberal (infundibulo-tuberal) region
 Posterior hypothalamic (mammillary regions) (Moore et al., 2018)

Hypothalamic nuclei are located within these specific regions and zones, which
include the following:

Region Area Nucleus Function

Anterior Preoptic Preoptic nucleus Thermoregulation

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(supraoptic)
Anterior Preoptic Medial preoptic Contains the
(supraoptic) nucleus sexually
dimorphism
nucleus, which
releases GnRH,
differential
development
between sexes is
based upon in
utero testosterone
level.
Anterior Preoptic Supraoptic nucleus Vasopressin and
(supraoptic) oxytocin release.
Anterior Medial Paraventricular Corticotropin-
(suproptic) nucleus releasing hormone
and thyrotropin-
releasing hormone
release.
Anterior((Supraoptic) Medial Anterior Thermoregulation
hypothalamic Sweating
nucleus Thyrotropin
inhibition
Anterior Medial Suprachiasmatic Circadian rhythms
(supraoptic) nucleus
Anterior Lateral Lateral nucleus Primary source of
(supraoptic) orexin neurons

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 that project
throughout the
brain and spinal
cord.
Tuberal Medial Dorsomedial Heart rate.
(middle) hypothalamic Gastrointestinal
nuclei stimulation.
Tuberal Medial Ventromedial Satiety.
(middle) nucleus Neuroendocrine
control.
Tuberal Medial Arcuate nucleus Growth-hormone
(middle) releasing
hormone.
Feeding.
Tuberal Lateral Lateral nucleus
Tuberal Lateral Lateral tuberal
nucleus
Mammillary Medial Mammillary nuclei Memory.
(posterior)
Mammillary Medial Posterior nucleus Vasopressin
Mammillary Lateral Lateral nucleus Primary source of
orexin neurons
that project
throughout the
brain and spinal
cord.
Mammillary Lateral Tuberomammillar Learning.

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 (posterior) y nucleus Memory.
Wakefulness and
attention.
1.1.1 Embryology

The hypothalamus originates from the neural tube during embryonic development.
It arises from the diencephalon, specifically the ventral portion. Around the third
week of development, the neural tube undergoes differentiation into various brain
regions, including the diencephalon. Within the diencephalon, the hypothalamus
forms as a result of complex signaling interactions between different signaling
centers and gradients of morphogens (Moore et al., 2020).

As development progresses, the hypothalamus becomes further subdivided into

various nuclei and regions, each with distinct functions (Larsen, 2017).

1.2 Anatomy Of the Pituitary Gland

The pituitary gland sits atop the base of the skull in a concavity within the
sphenoid bone called the sella turcica or the hypophyseal fossa, immediately below
the hypothalamus and optic chiasm. The pituitary gland measures 12mm in coronal
diameter, 8mm in AP diameter and 9mm high (Drake et al., 2020).

Fig. 2 Anatomy of the pituitary gland (Walizai, 2008)

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The pituitary gland is divided into 2 parts:

 Anterior pituitary(adenohypophysis)
 Posterior pituitary(neurohypophysis)

Anterior pituitary: the largest part of the gland and is responsible for synthesis and
release of most pituitary hormones.

It is divided into3 parts:

o Pars distalis: the largest part and it arises from the anterior wall of Rathke
pouch. It is composed of cords of epithelial cells individually specialized to
secrete trophic hormones acting on various target organs.
o Pars intermedia: this is a thin layer of epithelial cells located between pars
distalis and posterior pituitary. It arises from the posterior wall of Rathke
pouch and contains vestigial lumina of Rathke pouch which appears as
narrow vesicles of variable length.
o Pars tuberalis: the part of adenohypophysis which surrounds the anterior
aspect of the infundibular stalk (Drake et al., 2020).

Posterior pituitary: this is a direct extension from the hypothalamus, connected to it

via infundibular stalk, which is also considered part of the neurohypophysis. The
infundibulum extends from the tuber cinereum and pierces the diaphragm sella
before being surrounded by pars tuberalis.

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Fig. 3 photomicrograph of the pituitary gland (Wolters, 2020)

Relations

The pituitary gland is located within the sella turcica and has complex relations:

o Inferiorly: sphenoid sinus and inferior intercarvenous sinus.

o Laterally: carvenous sinuses and its content
o Posteriorly: posterior intercarvenous sinus and dorsum sellae.
o Anteriorly: anterior intercarvenous sinus and anterior clinoid process.
o Superiorly: diaphragm sellae and hypophyseal cistern (Moore et al., 2018).

There are different hormone producing cells in both the anterior and posterior
lobes of the pituitary gland.

Anterior lobe cells are divided based on their reaction to stain into:

 Acidophilic cells
 Basophilic cells
 Chromophobe cells

Acidophilic cells include:

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  Somatotrophs (50%of anterior lobe); which release growth hormone (Dalley
& Agur, 2018).
 Lactotrophs (15-20%); which release prolactin (Dalley and Agur, 2018).

Basophilic cells include:

Corticotrophs (20%); which release adrenocorticotropin.

Thyrotrophs (5%); which release thyroid stimulating hormone.

Gonadotrophs (10%); which release follicle stimulating hormone and luteinizing

hormone (Dalley and Agur, 2018).

Chromophobe cells are one of the three cell stain types present in the anterior and
intermediate lobes of the pituitary gland. It doesn’t stain readily and appears
relatively pale under the microscope (Dalley and Agur, 2018).

Posterior lobe contains an intrinsic population of cells called pituicyte, the

posterior lobe stores and releases oxytocin and vasopressin (antidiuretic hormone),
which are produced by the hypothalamus, these hormones are crucial for functions
such as such as water balance and uterine contractions during child birth
(Standring, 2016).

1.3 Gross Anatomy of the Testes

The testes are the male gonads responsible for producing sperm and testosterone.
They are paired organs located within the scrotum, which is an external pouch of
skin that hangs outside the abdominal cavity, maintaining a temperature slightly
cooler than body temperature, essential for effective spermatogenesis (Standring,
2016).

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 Fig. 4 gross anatomy of the testes (Kumar et al., 2013)

Shape and Size: Each testis is ovoid in shape, measuring approximately 4-5 cm in
length, 2.5 cm in width, and 3 cm in anteroposterior diameter, weighing around 15-
25 grams (Standring, 2016).

Testicular Coverings: The testes are covered by several layers:

o Tunica Vaginalis: A serous membrane derived from the peritoneum, which

has a parietal and visceral layer.

o Tunica Albuginea: A thick, fibrous capsule that encases the testis,

providing structural support. It extends inward to form septa that divide the
testis into lobules.

o Tunica Vasculosa: A layer of vascular connective tissue lining the inner

surface of the tunica albuginea (Young et al., 2014).

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Fig. 5 photomicrograph showing the histoarchitecture of the testes. (Ryan et al., 2017)
Veterinary histology (Ryan et al., 2017).

Internal Structure: Internally, the testis is divided into approximately 250 lobules
by septa from the tunica albuginea. Each lobule contains 1-4 seminiferous tubules,
where spermatogenesis occurs. The seminiferous tubules converge to form the rete
testis, which drains into the efferent ductules leading to the epididymis (Young et
al., 2014).

1.3.1 Histology of the Testes

Histologically, the testis is composed of several cell types and structures essential
for its function.

Seminiferous Tubules: The site of sperm production, these tubules are lined by a
complex stratified epithelium that includes:

 Spermatogenic Cells: Cells in various stages of development, from

spermatogonia to spermatids.

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  Sertoli Cells: act as supporting cells that nourish developing sperm cells
and form the blood-testis barrier. It also protect germ cells from
autoimmune reactions (Young et al., 2014).

 Leydig Cells: it is located in the interstitial tissue between seminiferous

tubules, these cells produce testosterone in response to luteinizing hormone
(LH) stimulation (Young et al., 2014).

 Myoid Cells: Surrounding the seminiferous tubules, they are contractile

cells that aid in the transport of spermatozoa through the tubules (Young et
al., 2014).

1.3.2 Embryology of the Testes

The embryological development of the testes begins early in gestation and involves
several key stages.

Gonadal Ridge Formation: The testes originate from the genital ridges, which form
during the fifth week of embryonic development. Primordial germ cells migrate
from the yolk sac to the genital ridges (Moore et al., 2018).

Sex Differentiation: The presence of the SRY gene on the Y chromosome triggers
the differentiation of the undifferentiated gonads into testes around the seventh
week of development. Sertoli cells differentiate first and secrete anti-Müllerian
hormone (AMH), leading to the regression of the Müllerian ducts, precursors to
female reproductive structures (Moore et al., 2018).

Testis Descent: Testicular descent occurs in two phases:

 Transabdominal Phase: Guided by the gubernaculum, the testes move from

the posterior abdominal wall to the deep inguinal ring.

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  Inguinoscrotal Phase: The testes then pass through the inguinal canal and
into the scrotum. This process is influenced by androgens and completed
by the time of birth (Moore et al., 2018).

1.4 Spermatogenesis

Spermatogenesis is the process by which male gametes, or sperm cells, are

produced in the testes. This process involves several stages, starting from a germ
cell and resulting in mature spermatozoa.

Steps of Spermatogenesis

Fig. 6 diagram showing the process of spermatogenesis (www. Shaala.com)

1. Spermatogonia Phase (Mitosis);

Spermatogonia: The process begins with spermatogonia, which are diploid stem
cells located in the seminiferous tubules of the testes. Spermatogonia undergo
mitotic divisions to produce more spermatogonia. There are two types of

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spermatogonia; type A which acts as stem cells, and type B which differentiate into
primary spermatocytes (Goel and Dullo, 2012).

2. Meiotic Phase (Meiosis I and II):

 Primary Spermatocytes: Type B spermatogonia develop into primary

spermatocytes, which are still diploid cells. These cells enter the first
meiotic division (meiosis I) (Russell et al., 1990).

 Secondary Spermatocytes: After meiosis I, primary spermatocytes divide to

form two haploid secondary spermatocytes. Each secondary spermatocyte
contains half the number of chromosomes (haploid) (Russell et al., 1990).

 Spermatids: Secondary spermatocytes undergo the second meiotic division

(meiosis II) to produce spermatids. Each secondary spermatocyte gives rise
to two spermatids, resulting in four spermatids per primary spermatocyte.
Spermatids are haploid and have half the genetic material of the original
spermatogonia (Goel and Dullo, 2012).

3. Spermiogenesis (Transformation):

 Spermatids to Spermatozoa: Spermiogenesis is the process where

spermatids transform into mature spermatozoa. This involves several
morphological changes:

 Condensation of Nucleus: The spermatid nucleus condenses and

elongates.

 Acrosome Formation: The Golgi apparatus forms the acrosome, a cap-like

structure that covers the anterior part of the nucleus.

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  Flagellum Development: The centrioles give rise to the flagellum, which
will become the tail of the sperm.

 Cytoplasm Reduction: Excess cytoplasm is shed as residual bodies and

phagocytosed by Sertoli cells (Silber, 2018).

 Spermiation: mature spermatozoa are released into the lumen of the

seminiferous tubules, a process known as spermiation (Silber, 2018).

4. Hormonal Regulation

The entire process of spermatogenesis is regulated by hormones such as follicle-

stimulating hormone (FSH) and luteinizing hormone (LH), which are secreted by
the pituitary gland. Testosterone, produced by Leydig cells in the testes, also plays
a crucial role in promoting spermatogenesis (Cheng and Mruk, 2010).

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 CHAPTER TWO

2.1 Anatomy of the HPG Axis

The hypothalamic-pituitary-gonadal (HPG) axis is a critical regulatory system that

governs reproductive function and sexual development. This axis involves a
complex interplay between the hypothalamus, pituitary gland, and gonads, each
contributing distinct anatomical and functional roles (Ganong, 2005).

1. Hypothalamus: The hypothalamus is located at the base of the brain and acts as
the control center of the HPG axis. It synthesizes and releases gonadotropin-
releasing hormone (GnRH) in a pulsatile manner. GnRH neurons are primarily
situated in the preoptic area of the hypothalamus and project their axons to the
median eminence, where GnRH is secreted into the hypophyseal portal system
(Swanson, 2000).

2. Pituitary Gland: The pituitary gland, often referred to as the master gland, is
located beneath the hypothalamus in the sella turcica of the sphenoid bone. It
comprises two lobes: the anterior and posterior pituitary. The anterior pituitary, or
adenohypophysis, responds to GnRH by secreting two key gonadotropins:
luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These
hormones are released into the systemic circulation and target the gonads (Ganong,
2005).

3. Gonads (testes): In males, the gonads are the testes, located in the scrotum. LH
stimulates Leydig cells in the testes to produce testosterone, while FSH acts on
Sertoli cells within the seminiferous tubules to support spermatogenesis (Moore
and Persaud, 2003).

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2.2 Hypothalamo-Hypophyseal Portal System

The hypothalamo-hypophyseal portal system is a specialized vascular network that

facilitates direct communication between the hypothalamus and the anterior
pituitary gland. This system plays a crucial role in the regulation of endocrine
functions by transporting hypothalamic hormones to the anterior pituitary, thereby
modulating its secretory activity (Ganong, 2005).

Anatomically, the hypothalamo-hypophyseal portal system begins with the primary

capillary plexus located in the median eminence of the hypothalamus.
Neurosecretory cells in the hypothalamus release hormones such as gonadotropin-
releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), and
corticotropin-releasing hormone (CRH) into this plexus. These hormones are then
carried by portal veins, which descend along the pituitary stalk to the secondary
capillary plexus in the anterior pituitary (Knobil and Neill, 2006).

Fig. 7 diagram showing the hypophyseal portal system (Fernandes, 2022)

Within the anterior pituitary, the hormones released from the hypothalamus
influence the secretion of various pituitary hormones. For example, GnRH
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stimulates the release of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH), while TRH prompts the secretion of thyroid-stimulating hormone
(TSH). This direct vascular connection ensures that hypothalamic hormones reach
their target cells in the anterior pituitary rapidly and in high concentrations, which
is essential for the precise regulation of pituitary hormone output (Ganong, 2005).

The efficiency and specificity of the hypothalamo-hypophyseal portal system are

vital for maintaining homeostasis and orchestrating complex physiological
processes, such as growth, metabolism, and reproduction (Knobil and Neill, 2006).

2.2.1 Vessels Involved in the Hypothalamo-Hypophyseal Portal System

The hypothalamo-hypophyseal portal system consists of a unique arrangement of

blood vessels that directly link the hypothalamus to the anterior pituitary gland,
enabling efficient hormonal communication. This vascular system includes the
primary capillary plexus, portal veins, and the secondary capillary plexus (Knobil
and Neill, 2006).

1. Primary Capillary Plexus: This network of fenestrated capillaries is located in

the median eminence of the hypothalamus. Neurosecretory cells in the
hypothalamus release hormones such as gonadotropin-releasing hormone (GnRH)
into this capillary bed. The fenestrated nature of these capillaries allows for the
easy passage of hormones into the blood (Ganong, 2005).

2. Portal Veins: From the primary capillary plexus, the blood containing
hypothalamic hormones is collected into long portal veins. These veins travel
down the pituitary stalk and connect to the anterior pituitary. The design of these
portal veins ensures that hormones released from the hypothalamus are transported
directly and efficiently to the anterior pituitary without dilution in the systemic
circulation (Knobil and Neill, 2006).

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3. Secondary Capillary Plexus: Upon reaching the anterior pituitary, the portal
veins branch out into the secondary capillary plexus. This capillary network
disperses the hypothalamic hormones throughout the anterior pituitary, where they
interact with specific receptors on pituitary cells, regulating the secretion of
hormones such as luteinizing hormone (LH), follicle-stimulating hormone (FSH),
thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH)
(Ganong, 2005).

This specialized vascular arrangement allows for precise and rapid hormonal
regulation, crucial for maintaining the body's homeostatic balance and coordinating
complex endocrine functions.

2.3 Hormonal Communication of the Hypothalamic-Pituitary-Gonadal (HPG)

Axis

The hypothalamic-pituitary-gonadal (HPG) axis governs reproductive function

through intricate hormonal interactions that coordinate the production and release
of gonadal hormones essential for fertility and sexual development (Ganong,
2005).

1. Hypothalamus: The HPG axis begins with the hypothalamus, which synthesizes
and releases gonadotropin-releasing hormone (GnRH). GnRH travels via the
hypothalamo-hypophyseal portal system to the anterior pituitary gland (Knobil and
Neill, 2006).

2. Anterior Pituitary: Upon reaching the anterior pituitary, GnRH stimulates the
secretion of two key gonadotropic hormones: luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). These hormones are released into the systemic
circulation and target the gonads—testes in males and ovaries in females (Ganong,
2005).

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3. Gonads: In males, LH acts on Leydig cells within the testes to stimulate the
production and secretion of testosterone, which is essential for spermatogenesis
and the development of male secondary sexual characteristics. FSH acts on Sertoli
cells to support spermatogenesis within the seminiferous tubules (Moore and
Persaud, 2003). In females, LH and FSH stimulate the ovarian follicles to produce
estrogen and progesterone, which regulate the menstrual cycle and support
pregnancy (Moore and Persauad, 2003).

4.Feedback Mechanisms: Testosterone and estrogen, produced by the gonads, exert

negative feedback on the hypothalamus and anterior pituitary, modulating the
secretion of GnRH, LH, and FSH to maintain hormonal balance and regulate
reproductive function (Ganong, 2005).

2.4 Neuronal Communication of the Hypothalamic-Pituitary-Gonadal (HPG)

Axis

The neuronal communication within the hypothalamic-pituitary-gonadal (HPG)

axis involves complex interactions between hypothalamic neurons, pituitary cells,
and gonadal tissues, regulating reproductive processes and hormone secretion
(Ganong, 2005).

1. Hypothalamic Neurons: Within the hypothalamus, specialized neurons

synthesize and release gonadotropin-releasing hormone (GnRH). These neurons
are located primarily in the preoptic area and project their axons to the median
eminence, where GnRH is released into the hypothalamo-hypophyseal portal
system (Knobil and Neill, 2006).

2. Hypophyseal Portal System: GnRH travels through the portal veins to the
anterior pituitary gland. This vascular system ensures that GnRH reaches the

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anterior pituitary rapidly and in high concentrations, facilitating the stimulation of
gonadotropin secretion (Ganong, 2005).

3. Anterior Pituitary: Upon reaching the anterior pituitary, GnRH stimulates the
synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) from gonadotroph cells. LH and FSH are released into the
systemic circulation and act on the gonads (testes in males and ovaries in females)
(Knobil and Neill, 2006).

4. Gonadal Feedback: Gonadal hormones, such as testosterone and estrogen,

produced in response to LH and FSH, provide feedback to the hypothalamus and
pituitary gland. This feedback mechanism regulates the secretion of GnRH, LH,
and FSH, maintaining hormonal balance and ensuring proper reproductive function
(Ganong, 2005).

Fig. 8 diagram showing the neuronal interaction of the HPG axis (Agnieszka et al., 2023)

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 CHAPTER THREE

3.1 Regulation of Spermatogenesis by the Hypothalamic-Pituitary-Gonadal

(HPG) Axis
Spermatogenesis, the complex process of sperm production, is tightly regulated by
the hypothalamic-pituitary-gonadal (HPG) axis through precise hormonal control
mechanisms. Research has elucidated the role of key hormones in this regulatory
process, highlighting their impact on testicular function and sperm development
(Kretzer et al., 2010).

1. Gonadotropin-Releasing Hormone (GnRH): GnRH is synthesized and released

by the hypothalamus into the bloodstream and stimulates the secretion of
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the
anterior pituitary gland (O’Shaughnessy et al., 2002).

The GnRH stimulate the gonadotroph of the adenohypophysis to secrete follicle-

stimulating hormone and luteinizing hormone.

2. Luteinizing Hormone (LH): LH acts on Leydig cells in the testes to induce the
production and secretion of testosterone, which is crucial for spermatogenesis
(O'Shaughnessy et al., 2002).

3. Follicle-Stimulating Hormone (FSH): FSH plays a pivotal role in

spermatogenesis by stimulating Sertoli cells within the seminiferous tubules.

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Sertoli cells support germ cell development and provide the necessary
microenvironment for sperm maturation (Matzuk and Lamb, 2008).

4. Testosterone and Sertoli Cell Function: Testosterone produced by Leydig cells

exerts both paracrine and endocrine effects on Sertoli cells, enhancing their ability
to support spermatogenesis. Sertoli cells in turn, produce factors like inhibin and
activin, which regulate FSH secretion and influence germ cell development
(Matzuk and Lamb, 2008).

5. Feedback Mechanisms: Testosterone and inhibin provide negative feedback to

the hypothalamus and pituitary gland, modulating the secretion of GnRH, LH, and
FSH to maintain hormonal balance and optimize spermatogenesis according to
physiological demands (O’Shaughnessy et al., 2002; Matzuk and Lamb, 2008).

3.2 Effects of Hypothalamic Hormones on the Anterior Pituitary and Testes

Hormones released by the hypothalamus play a crucial role in regulating the

anterior pituitary gland and subsequently affect testicular function. Research has
elucidated the mechanisms through which hypothalamic hormones exert their
influence on these endocrine organs.

1. Gonadotropin-Releasing Hormone (GnRH): GnRH synthesized in the

hypothalamus, stimulates the anterior pituitary gland to release two key
gonadotropic hormones, luteinizing hormone (LH), and follicle-stimulating
hormone (FSH). These hormones are released into the systemic circulation and act
on the gonad(testes) in males (O’Shaughnessy et al., 2002).

2. Anterior Pituitary: GnRH binds to specific receptors on gonadotrophs in the

anterior pituitary, triggering intracellular signaling pathways that result in the
synthesis and secretion of LH and FSH (O’Shaughnessy et al., 2002).

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3. Testes: LH binds to receptors on Leydig cells within the testes, stimulating them
to produce and release testosterone. FSH binds to receptors on Sertoli cells,
promoting spermatogenesis within the seminiferous tubules (O’Shaughnessy et al.,
2002).

3.2.1 Effects 0f Gonadotropin on the Gonads

A. Effects of Luteinizing Hormone (LH) on Leydig Cells

Luteinizing hormone (LH) plays a crucial role in regulating testosterone

production by Leydig cells within the testes.

1. Binding and Activation: LH binds to specific receptors located on the surface of

Leydig cells in the testes (Manna et al., 2013). This binding triggers a series of
intracellular signaling cascades, including the activation of adenylate cyclase and
the subsequent increase in cyclic adenosine monophosphate (cAMP) levels within
Leydig cells (Manna et al., 2013).

2. Steroidogenesis: Elevated cAMP levels stimulate the synthesis of steroidogenic

enzymes, particularly cholesterol side-chain cleavage enzyme (P450scc) and 17α-
hydroxylase/17,20-lyase (CYP17A1). These enzymes are essential for converting
cholesterol into testosterone (Manna et al., 2013).

3. Testosterone Production: The increased activity of steroidogenic enzymes

enhances the rate of testosterone production by Leydig cells. Testosterone, in turn,
acts on target tissues such as Sertoli cells and male accessory organs to promote
spermatogenesis and maintain secondary sexual characteristics (Manna et al.,
2013).

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4. Feedback Regulation: Testosterone produced by Leydig cells exerts negative
feedback on the hypothalamus and anterior pituitary gland, inhibiting the secretion
of GnRH and LH. This feedback mechanism helps maintain hormonal balance and
regulate testosterone levels within physiological ranges (Manna et al., 2013).

Fig. 9 diagram showing the interactions of the HPG axis in regulation of

spermatogenesis (Shah et al., 2021)

B. Effects of Follicle-Stimulating Hormone (FSH) on Sertoli cells

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Follicle-stimulating hormone (FSH) plays a crucial role in regulating
spermatogenesis by exerting specific effects on Sertoli cells within the
seminiferous tubules of the testes.

1. Binding and Activation: FSH binds to specific receptors located on the surface
of Sertoli cells (Cheng and Mruk, 2010). This binding initiate signaling pathways
that involve the activation of cyclic adenosine monophosphate (cAMP) and protein
kinase A (PKA) within Sertoli cells.

2. Support for Germ Cell Development: FSH stimulates Sertoli cells to secrete
various factors essential for germ cell development, including growth factors,
cytokines, and androgen-binding protein (ABP) (Cheng & Mruk, 2010). ABP
binds testosterone, concentrating it within the seminiferous tubules to support
spermatogenesis.

3. Regulation of Spermatogenesis: FSH regulates the proliferation and

differentiation of germ cells within the seminiferous epithelium. It promotes the
formation of tight junctions between Sertoli cells, which are crucial for creating the
blood-testis barrier and providing a protected microenvironment for
spermatogenesis (Cheng and Mruk, 2010).

4. Feedback Regulation: Testosterone and inhibin, produced by Leydig cells and

Sertoli cells respectively, provide feedback to the hypothalamus and anterior
pituitary gland to regulate FSH secretion. Inhibin selectively inhibits FSH
secretion, ensuring that spermatogenesis proceeds at an appropriate rate (Cheng
and Mruk, 2010).

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 CHAPTER FOUR

4.1 Disorders Associated with the Hypothalamic-Pituitary-Gonadal (HPG)

Axis
The HPG axis is critical for regulating reproductive function, and disruptions in its
normal functioning can lead to various disorders affecting fertility and sexual
development. Several disorders are associated with abnormalities in the HPG axis,
each impacting different stages of reproductive physiology (Palmert and Dunkel,
2012).

4.1.1 Male Hypogonadism

Male hypogonadism is a condition characterized by the body's inability to produce

adequate levels of testosterone or sperm, or both, due to issues with the testes or
the hypothalamic-pituitary axis. This condition can affect various physiological
functions, including sexual development, muscle mass, bone density, and overall
health (Basin et al., 2018)

Types of Male Hypogonadism

There are two primary types of male hypogonadism:

A. Primary Hypogonadism (Hypergonadotropic Hypogonadism): This type occurs

due to problems within the testes leading to low testosterone levels despite high
levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
(Bhasin et al., 2018).

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Causes:

 Genetic Disorder: the common genetic causes is Klinefelter syndrome (XXY

syndrome).

 Infections: infections like Mumps orchitis can damage the testes.

 Trauma or Surgery: Physical damage or surgical removal of the testes.

 Toxins and Medications: Exposure to chemotherapy or radiation therapy

(Wang et al., 2018).

B. Secondary Hypogonadism (Hypogonadotropic Hypogonadism): This type

occurs due to issues with the hypothalamus or pituitary gland, leading to
insufficient production of gonadotropins (LH and FSH), which in turn causes low
testosterone levels (Bhasin et al., 2018).

Causes:
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  Pituitary Disorders: Tumors of the pituitary gland, surgery, or radiation.

 Hypothalamic Disorders: Kallmann syndrome, a genetic condition

affecting the hypothalamus.

 Systemic Diseases: Obesity, diabetes, and chronic illnesses.

 Medications: Opioids and glucocorticoids.

 Stress and Malnutrition: Psychological stress and poor nutrition can

affect hypothalamic function (Wang et al., 2018).

Symptoms of Male Hypogonadism: The symptoms can vary depending on the age
of onset;

 Prepubertal Onset: Delayed or absent puberty, reduced testicular and penile

growth, lack of secondary sexual characteristics (e.g., facial hair, deepening
of the voice) and eunuchoid body proportions (long limbs compared to
trunk) (Nieschlag et al., 2010).

 Adult Onset Decreased libido and erectile dysfunction, infertility, decreased

muscle mass and strength, increased body fat and gynecomastia,
osteoporosis and decreased bone mineral density, fatigue, depression, and
cognitive difficulties (Nieschlag et al., 2010).

4.1.2. Delayed Puberty in Males

Delayed puberty in males is characterized by the absence or incomplete

development of secondary sexual characteristics by an age at which 95% of boys
have begun sexual maturation. Typically, this is defined as the lack of testicular
enlargement (to a volume of ≥4 mL) by age 14 (Palmert and Dunkel, 2012).

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Causes of Delayed Puberty: The causes of delayed puberty in males can be broadly
categorized into two groups: constitutional delay and pathological causes.

A. Constitutional Delay of Growth and Puberty (CDGP): is the most common

cause of delayed puberty in boys. It is considered a variation of normal
development where there is a temporary delay in skeletal growth and sexual
maturation. Boys with CDGP are often shorter than their peers and have delayed
bone age. They eventually undergo spontaneous puberty and reach normal adult
height (Palmert and Dunkel, 2012).

B. Pathological Causes:

 Hypogonadotropic Hypogonadism (Central or Secondary Hypogonadism):

This condition is due to insufficient secretion of gonadotropins (LH and
FSH) from the hypothalamus or pituitary gland. This can be caused by
different factors like;

 Genetic Disorders: Kallmann syndrome, which is associated with

anosmia (lack of sense of smell).

 Chronic Illnesses: Conditions such as chronic renal insufficiency,

inflammatory bowel disease, and cystic fibrosis.

 Malnutrition: Conditions such as anorexia nervosa or chronic

undernutrition.

 Functional Disorders: High physical activity levels or severe

psychological stress.

 Tumors: Pituitary or hypothalamic tumors (Styne and Grumbach, 2016).

The primary symptoms of delayed puberty in males include:

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  Lack of Testicular Enlargement: No increase in testicular volume by age 14.

 Absence of Secondary Sexual Characteristics: Lack of pubic hair, deepening

of the voice, and muscle development.

 Growth Delay: Boys may be shorter than their peers with delayed growth
spurts.

 Psychosocial Impact: Delayed puberty can lead to psychosocial distress, low

self-esteem, and social withdrawal due to the disparity in physical
development compared to peers (Palmert and Dunkel, 2012).

4.1.3. Hyperprolactinemia in Males

This is a condition characterized by elevated levels of prolactin in the blood.

Prolactin is a hormone produced by the anterior pituitary gland and is primarily
associated with lactation in females. However, it also has several other functions,
including roles in metabolism, regulation of the immune system, and development
of the reproductive system. In males, elevated prolactin levels can have significant
health implications (Molitch, 2017).

Hyperprolactinemia in males can be caused by several factors, including:

 Pituitary Tumors (Prolactinomas): The most common cause of elevated

prolactin levels in both males and females is a prolactin-secreting pituitary
adenoma (Molitch, 2017). These benign tumors can increase prolactin
production significantly.

 Medications: Certain medications can elevate prolactin levels, including

antipsychotics, antidepressants, and antihypertensives (Melmed et al.,
2011).

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  Hypothyroidism: Low thyroid hormone levels can lead to increased
prolactin release due to increased thyrotropin-releasing hormone (TRH)
stimulation of the pituitary gland (Serri et al., 2003).

 Other Causes: Other causes include chronic renal failure, chest wall injuries
or irritations, and idiopathic hyperprolactinemia, where no specific cause is
identified.

Symptoms:

 Hypogonadism: This manifests as decreased testosterone levels, leading to

reduced libido, erectile dysfunction, and infertility (Melmed et al., 2011).

 Gynecomastia: Development of breast tissue in males.

 Galactorrhea: Although rare, some males may experience milk secretion

from the breast (Serri et al., 2003).

 Visual Impairment: Large pituitary tumors can compress adjacent structures,

leading to visual field defects.

4.1.4. Kallmann Syndrome in Males

This is a genetic disorder characterized by a failure to start or complete puberty

and an impaired sense of smell (anosmia or hyposmia). It is a form of
hypogonadotropic hypogonadism (HH), where the hypothalamus does not produce
sufficient gonadotropin-releasing hormone (GnRH), resulting in low levels of sex
hormones (Mitchell et al., 2011)

Causes: Kallmann syndrome is primarily caused by mutations in genes involved in

the development and function of GnRH neurons. The most commonly affected
genes include KAL1, FGFR1, FGF8, PROKR2, and PROK2 (Dodé and Hardelin,

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2009). These genetic mutations disrupt the migration of GnRH neurons from the
olfactory placode to the hypothalamus during embryonic development.

Symptoms:

 Delayed or Absent Puberty: This is often the first sign, characterized by a

lack of secondary sexual characteristics such as facial hair, deepening of the
voice, and growth of testes and penis (Bianco and Kaiser, 2009).

 Anosmia or Hyposmia: A reduced or absent sense of smell is a distinctive

feature of Kallmann syndrome.

 Other Symptoms: Some individuals may also have mirror movement of the
hands, hearing loss, renal agenesis, and cleft lip or palate (Mitchell et al.,
2011).

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 CHAPTER FIVE

Conclusion

The Hypothalamic-Pituitary-Gonadal (HPG) axis plays a crucial role in regulating

spermatogenesis, the process by which sperm are produced and matured in the
testes. This axis involves a complex interplay of hormones, primarily GnRH
(Gonadotropin-Releasing Hormone), FSH (Follicle-Stimulating Hormone), LH
(Luteinizing Hormone), and testosterone, which work together to ensure the proper
development and function of male reproductive cells.

GnRH, secreted by the hypothalamus, stimulates the anterior pituitary gland to

release FSH and LH. FSH acts on the Sertoli cells in the testes, promoting the
nourishment and maturation of sperm cells, while LH stimulates Leydig cells to
produce testosterone, the primary male sex hormone. Testosterone not only
supports spermatogenesis but also provides feedback to the hypothalamus and
pituitary to regulate the levels of GnRH, FSH, and LH, maintaining a balanced
hormonal environment.

Disruptions in the HPG axis can lead to impaired spermatogenesis and

consequently, male infertility. Conditions such as hypogonadism,
hyperprolactinemia, and various genetic disorders.

Recommendation

Aphrodisiac herbs can enhance the role of the Hypothalamic-Pituitary-Gonadal

(HPG) axis on spermatogenesis through several mechanisms. These herbs often

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contain bioactive compounds that can influence hormonal balance, increase the
production of critical hormones, and improve overall reproductive health.

1. Stimulation of GnRH Secretion: Some aphrodisiac herbs can stimulate the

hypothalamus to release more Gonadotropin-Releasing Hormone (GnRH).
Increased GnRH levels prompt the anterior pituitary gland to produce more
Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH).

2. Enhancement of FSH and LH Production: By promoting the secretion of FSH

and LH from the pituitary gland, aphrodisiac herbs can directly influence
spermatogenesis. FSH acts on Sertoli cells to support sperm cell development,
while LH stimulates Leydig cells to produce testosterone.

3. Boosting Testosterone Levels: Many aphrodisiac herbs are known to enhance

testosterone production. Higher testosterone levels contribute to improved
spermatogenesis by stimulating the testes directly and providing the necessary
androgenic support for sperm maturation.

4. Improving Blood Flow: Improved blood circulation, a common benefit of many

aphrodisiac herbs, can enhance nutrient and oxygen delivery to the testes, thereby
supporting the environment needed for effective spermatogenesis.

5. Antioxidant Properties: Aphrodisiac herbs often possess antioxidant properties,

which help protect the testes from oxidative stress. Reducing oxidative stress can
improve sperm quality and count.

6. Balancing Hormones: Some herbs help balance overall hormone levels, reducing
the risk of hormonal imbalances that can impair spermatogenesis. They might
modulate the activity of enzymes involved in hormone synthesis and metabolism.

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7. Reducing Stress: Stress can negatively impact the HPG axis and
spermatogenesis. Aphrodisiac herbs often have adaptogenic properties, helping to
reduce stress and its adverse effects on reproductive health.

Examples of Aphrodisiac Herbs and Their Effects:

Carpolobia alba: this herb is known for its adrogenic effects and it has been
proven by different researcher that it improves reproductive functions in male.

Tribulus terrestris: Known to boost LH and testosterone levels, promoting

spermatogenesis.

Maca root: May enhance libido and improve sperm quality by balancing hormone
levels.

Ginseng: Known for its ability to stimulate the hypothalamus and improve overall
hormonal balance, benefiting spermatogenesis.

In conclusion, aphrodisiac herbs can support the HPG axis and spermatogenesis by
stimulating hormone production, improving blood flow and testicular function,
reducing oxidative stress, and balancing overall hormonal levels. These effects
collectively contribute to enhanced reproductive health and fertility.

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