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albuginea
Te
Epididymis
seminiferous tubule
Spermatocytes
a
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M. Ciaccio et al.
Lumen of the
Leydig cells
Deferent duct
Serous cavity
Rete testis
Tunica
vaginalis
Tunica
Septa
sticular
lobules
Seminiferous
tubule
Fig. 25.25 Anatomical structure of the testis. (Copyright EDISES
2021. Reproduced with permission)
Spermatids
Spermatogoni
Spermatocytes
Haploid
spermatozoa
Sertoli cells
Fig. 25.26 Anatomical section of the seminiferous tubule. (Copyright
EDISES 2021. Reproduced with permission)
Blood vessel
lumen
Physiology
functions as a spermatozoa storage. Additionally, it
destroys “aged” spermatozoa or those showing structural
anomalies. The epididymis is connected, through the ductus
deferens, to the ejaculatory duct from which it receives
thesecretionfrom seminal vesicles, which are located behind
the bladder and the prostate. The ejaculatory duct pours its
contents into the prostatic urethra, where the prostatic secretion also ows.
The seminiferous tubules are formed mainly by two cell
types: germ cells and Sertoli cells. Germ cells are responsible for spermatogenesis; these cells are arranged in layers
in the wall of each tubule, according to a maturational
order, from the periphery to the center (spermatogonia,
spermatocytes, spermatids) (Fig.25.26). The most immature cells, spermatogonia, go through two phases during
their development; during the rst, called spermatogenesis,
DNA halving occurs, and through this phase, haploid cells,
called spermatids, are obtained. Spermatogenesis is followed by spermiogenesis, characterized by a series of
important morphological cellular changes, at the end of
which mature spermatozoa are obtained. The wall of the
tubules is covered by Sertoli cells, which support and nourish the germ cells. Between the seminiferous tubules are
also the interstitial or Leydig cells, which are responsible
for testosterone synthesis (Fig.25.26).
Male Hypothalamic-Pituitary-Gonadal Axis
Growth and sexual differentiation in the male result from a
complex feedback circuit involving the hypothalamus, pituitary, and gonads. Neurons of the lateral ventricles of the
hypothalamus synthesize and secrete the Gonadotropin
Releasing Hormone (GnRH). It is a decapeptide that, through
the pituitary peduncle, spills into the median eminence and
reaches the anterior pituitary, where it binds to its specic
receptors resulting in the release of Luteinizing Hormone
(LH) and, to a lesser extent, Follicle-stimulating hormone
(FSH) (Fig.25.27). GnRH is released in a pulsatile manner
every 60–90minutes, and this pulsatility is critical for the
normal functioning of the pituitary-gonadal axis.
Gonadotropins (FSH, LH) have two subunits: α and β.
The α subunit is common to all glycoprotein hormones
(FSH, LH, TSH, and hCG), while the β subunit is specic for
the different hormones. LH and FSH levels vary according to
the individual’s age: high at birth, decrease during growth,
low or undetectable levels throughout the prepubertal period,
and increasing in later stages of development. FSH binds
specic receptors on Sertoli cells, stimulating the synthesis
and release of inhibin and other factors essential for regulating spermatogenesis (Fig.25.27).
Inhibin is a heterodimeric protein hormone belonging to
the Transforming Growth Factor-β (TGF-β) superfamily. It
Hypothalamus
++
Leydig cells
Oestrone
Testosterone
Dihydrotestosterone (DHT)
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exists in two molecular forms: inhibin A and inhibin B,
derived from the combination of an α subunit and two β subunits (βA and βB). Both isoforms are required in gonadal
maturation processes in men and women. Inhibin B plays an
essential role in spermatogenesis and controls, via negative
feedback, the pituitary production of FSH. This feedback
GnRH
+
Anterior
pituitary
LH
Testis
Leydig cells Sertoli cells
Testosterone Activin
Positive feedback
Negative feedback
Fig. 25.27 Male hypothalamus-pituitary-gonad regulation. GnRH
gonadotropin-releasing hormone, LH luteinizing hormone, FSH
follicle- stimulating hormone. (Copyright EDISES 2021. Reproduced
with permission)
FSH
Inhibin
involves the inhibin B, which actsas anactivin antagonist.
Activin is structurally homologous to inhibinandstimulates
FSH synthesis (Fig.25.27).
Sertoli cells also produce Müllerian Inhibiting Substance
(MIS), which, duringmale genital apparatusdifferentiation,
will induce regression of Müllerian structures (fallopian
tubes, uterus, upper portion of the vagina).
Leydig cells react to the LH-induced stimulus by converting cholesterol, either from LDL or synthesized within the
cells, to pregnenolone and thento dehydroepiandrosterone
(DHEA), androstenedione or androstenediol, which will
eventually be converted to testosterone (Figs. 25.26 and
25.28). The testis produces 3–10mg per day of testosterone.
Once produced, testosterone can perform its functions by
binding androgen receptors or be converted, at the target tissues, into a more potent metabolite, dihydrotestosterone
(DHT), by the enzyme 5α-reductase, or into 17β-estradiol by
the enzyme aromatase (Fig.25.28).
Testosterone and estradiol exert a negative control mechanism on the hypothalamic-pituitary axis. Specically, testosterone inhibits the production of GnRH, FSH, and LH,
resulting in decreased production of testosterone by Leydig
cells; estradiol blocks the production of LH and FSH
(Fig.25.26). Estradiol is essential in regulating bone development (inhibitory action), epiphyseal closure, and lipid
metabolism; nally, it possesses a psychotropic action.
Testosterone is secreted in a pulsatile manner and circulates in the peripheral blood form bound to plasma proteins
(i.e.,SHBG and albumin) and, to a lesser extent, in free form.
Testosterone is responsible for sexual differentiation, developing and maintaining secondary sexual characteristics,
regulating erythropoiesis and libido control, and developing
muscle mass and bone structure. DHT, produced by the conversion of testosterone, androstenedione, and DHEA attarget tissues (mainly skin, liver, and urogenital tissues), is
responsible for sexual differentiation (induces the development of external genitalia), sebum production, prostate
development, and the appearance of hair. In addition to testosterone production, the testis synthesizes progesterone,
17-OH-progesterone, and androstenedione (D4).
Fig. 25.28 Synthesis of
testosterone, estradiol and
dihydrotestosterone in Leydig
cells and peripheral tissues.
(Copyright EDISES 2021.
Reproduced with permission)
Dehydroepiandrosterone
(DHEA)
Androstenediol
Androstenedione Androstenedione
Testosterone Testosterone
P450arom
P450arom
Estradiol
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M. Ciaccio et al.
Small amounts of testosterone are present several years
before puberty and produced in response to the adrenal
androgens DHEA and dehydroepiandrosterone sulfate
(DHEA-S), which are responsible for pubic and axillary hair
(adrenarche)appearance.
Testis Pathologies
Hypogonadism
Male hypogonadism is characterized by a dysfunction of the
hypothalamic-pituitary-gonadal axis marked by a testosterone decit and/or an impairment in spermatogenesis. There
are different clinical pictures due to congenital or acquired
causes. In the primary forms, testes are the organs primarily
affected and there is circulating testosterone decrease and
gonadotropin increase with impaired spermatogenesis
(hypergonadotropic hypogonadism). The alterations in testosterone synthesis are due to structural damage of the
Leydig cells, which is sometimes associated with a
deterioration of the seminiferous tubules leading to oligospermia or azoospermia. Testosterone deciency, in turn,
results in elevated levels of gonadotropins (FSH and LH) due
to testosterone’s failure to inhibit GnRH at the hypothalamic
level.
Primary hypogonadism can result from congenital,
acquired, and/or systemic disease-related causes
(Table25.27).
The most frequent congenital cause of hypergonadotropic
hypogonadism is Klinefelter syndrome. This disorder causes
dysgenesis of the seminiferous tubule and a 47,XXY karyotype. A rare form of hypogonadism results from mutations in
the androgen receptors; in this case, the phenotype presents a
partial or complete resistance to androgens.
Secondary hypogonadism is characterized by low testosterone levels, low or inappropriately normal gonadotropin
concentrations, and reduced spermatogenesis (hypogonadotropic hypogonadism). This condition is characterized by
Table 25.27 Causes of primary hypogonadism
Congenital causes Acquired causes
Klinefelter syndrome (XXY)
Microdeletions of the Y
chromosome
Mutations of the FSH receptor
Mutations of the LH receptor
Myotonic dystrophy
Cryptorchidism
Noonan syndrome
Bilateral anorchidia
FSH follicle-stimulating hormone, CRI chronic renal failure, LH luteinizing hormone
Orchitis
Bilateral surgical castration
Testicular trauma
Drugs, chemotherapy, ionizing
radiation
Hemochromatosis
General disorders (liver cirrhosis,
CRI)
Lymphoma or testicular cancer
Table 25.28
Congenital causes Acquired causes
Kallmann
syndrome
Prader-Willi
syndrome
Laurence-Moon
syndrome
Mutation of the β
LH chain
Mutation of the β
FSH chain
FSH follicle-stimulating hormone, GnRH gonadotropin releasing hormone, CRI chronic renal failure, LH luteinizing hormone
Causes of secondary hypogonadism
Panhypopituitarism
Hyperprolactinemia
Hemochromatosis
Hypothalamic or pituitary tumors
Drugs (opiates, glucocorticoids, GnRH agonists
or antagonists)
Acute or chronic diseases (obesity, eating
disorders, diabetes, stress, malnutrition, CRI)
inadequate production of FSH and LH by the hypothalamicpituitary axis and may be of congenital or acquired origin.
Most acute or chronic systemic diseases, e.g., chronic
renal failure, diabetes, anorexia nervosa, stress, malnutrition,
obesity, hyperprolactinemia, hemochromatosis, and neoplastic or non-neoplastic masses in the hypothalamic-pituitary
region, can induce gonadal hormone deciency (Table25.28).
Different clinical manifestations characterize androgenic
deciency, also depending on the degree and duration of the
deciency itself; in particular, a decrease in libido, erectile
dysfunction, cognitive decline, sleep disorders, mood
changes, reduction in lean body mass, increase in visceral
fat, testicular atrophy, osteopenia, and sparse body hair can
be observed. These individuals are predisposed to gynecomastia and present eunuchoid body proportions due to
delayed epiphysis welding and the continued growth of long
bones.
Late-Onset Hypogonadism
Late-Onset Hypogonadism (LOH) is a form of hypogonadism associated with aging, characterized by a reduction in
blood levels of androgens, with or without a reduction in
androgen receptor sensitivity. This clinical condition can
lead to signicant alterations in quality of life and dysfunction of various organs and systems, including sexual function. From about 30years of age, the total serum testosterone
level in men physiologically decreases by 1% per year. This
occurs due to several age-related mechanisms, including an
increase in the concentration of sex hormone–binding globulin (SHBG), which decreases circulating testosterone's free
and bioavailable. In addition, the secretion of pulsatile GnRH
decreases physiologically over time, attenuating the LH
response that will more mildly stimulate the testis to produce
and secrete testosterone. Generally, this process has a slow
progression that may increase due to chronic disease
or drugs. The reduction of testosterone leads to a clinical
conditions, overlapping with primitive hypogonadism, characterized by loss of muscle mass, osteopenia, loss of libido,
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365
and age-related cognitive decline. The term andropause
describes these age-dependent changes, although this is
improperly used, as there is no rapid and abrupt drop in
androgens but rather a slow and progressive change that has
no correspondence with the female menopausal period. LH
levels also undergo age-related changes, increasing over
time, suggesting a primary testicular dysfunction underpinning the decrease in androgen levels.
Laboratory Investigations
Basal Hormone Measurements
Gonadotropin
Plasma and serum are the samples of choice for gonadotropin and androgen measurement.
The evaluation of gonadotropins, FSH, and LH, provides
essential information on the origin of testicular dysfunction.
They are currently measured by immunouorometric or
electrochemiluminescence assays, characterized by a high
diagnostic sensitivity (Table25.29). The values obtained by
different methods vary considerably, and each technique has
a different reference range.
Since gonadotropin levels change throughout the day, it is
recommended that any pathologic or questionable results be
evaluated on a second blood collection.
Testosterone
Circulating testosterone is carried 40% by sex hormone–
binding globulin (SHBG) and 58% by albumin, while 2% is
free and represents the biologically active fraction. Since the
binding of testosterone to SHBG is very stable, only testosterone bound to albumin is bioavailable. “Bioavailable testosterone” refers to the proportion of free and albumin-bound
testosterone that can be cleaved and made available in target
tissues. Daily testosterone uctuations require venous sampling between 8 and 10a.m. However, several studies showed
Table 25.29 Reference values of the main hormones
Parameter Reference values
a
LH
(IU/L) 1.7–8.6
a
(IU/L) 1.5–12.4
FSH
Total Testosterone
18–49years
>50years
free Testosterone
Prolactin
a
Reference values using electrochemiluminescence method
b
Reference values using the ELISA method
a
a
(μg/L)
b
(ng/L) 3.84–34.17
(μg/L)
2.49–8.36
1.93–7.40
4.04–15.2
Table 25.30
levels
Elevated levels of SHBG
-Age
-Hyperthyroidism
-Hyperestrogenism
-Liver disorders
-HIV
-Antiepileptic drugs
Low levels of SHBG
-Obesity
-Insulin resistance and diabetes
-Hypothyroidism
-Nephrotic syndrome
-Glucocorticoids
-Androgens
-Progestogens
-Excess of GH
GH growth hormone, SHBG sex hormone–binding globulins
Conditions associated with altered circulating SHBG
that the circadian rhythm fades with age and, therefore, in the
elderly, this time window loses its signicance.
The assay of total testosterone (includingfree and proteinbound portion) is performed by electrochemiluminescent
immunometric method (Table 25.30) and liquid
chromatography- tandem mass spectrometry (LC-MS/MS).
Currently, LC-MS/MS is the best method, as it provides an
accurate and precise estimate of total testosterone levels with
high diagnostic sensitivity. However, alterations in SHBG
levels may affect total testosterone levels. In such a case, the
assay of free testosterone, i.e., the free portion representing
approximately 2% of circulating testosterone, is recommended. Several methods have been proposed to measure
the free fraction of testosterone. Equilibrium dialysis is the
gold standard for quantifying the biologically active form of
testosterone; however, it is a technique scarcely available in
most clinical laboratories.
For this reason, it is recommended to use computational
equations allowing free testosteroneevaluation usingSHBG,
albumin, and total testosterone. The values obtained using
the Vermeulen formula show a high correlation with those
obtained by equilibrium dialysis, representing a simple and
reliable indicator (Fig. 25.29). Alternatively, free testosterone can be measured by enzyme immunoassay (Table25.30).
Testosterone is also detectable in saliva at a concentration
comparable to free testosterone in serum; however, its assay
requires careful quality control because it may be subject to
severalartifacts.
Inhibin B
The evaluation of inhibin B reects the functionality of the
seminiferous tubules. Reduced inhibin B concentrations are
observed if spermatogenesis is impaired (e.g., after chemo-
366
TT
K
K
SBHG = SHBG concentration (mol/L)
FT
Alb = Albumin concentration (mol/L)
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TT = Ks · [SHBG] · FT/1 + (Ks· FT) +
+ Ka ·[Alb] · FT/1 + (Ka· FT) + FT
= Total Testosterone (mol/L)
= Association constant for T-SHBG binding (L/mol)
s
= Association constant for T-Albumin bond (L/mol)
a
= Free Testosterone (mol/L)
Fig. 25.29 Equation for calculating free and bioavailable testosterone
(Vermeulen’s formula). (Copyright EDISES 2021. Reproduced with
permission)
M. Ciaccio et al.
one or both testes to descend into the scrotal sac). The test
involves the administration of 5000IU of hCG intramuscularly and the dosage of testosterone at baseline and after
72hours. Leydig cell function is considered normal if testosterone levels increase by 1.5–2μg/L.This test is not recommended in adults because testosterone and gonadotropin
assays are sufcient for diagnosis. In young men with congenital anorchidia, no increase in testosterone levels is
observed after stimulation with hCG.Subjects with gonadotropin deciency respond poorly to hCG administration due
to a loss of sensitivity of Leydig cells.
Diagnosis andTherapy
therapy). The inhibin B assay is performed by ELISA
(Enzyme-Linked ImmunoSorbent Assay).
Prolactin
High prolactin levels may be associated with hypogonadotropic hypogonadism. Increased prolactin can be detectedin
prolactin-secreting tumors (prolactinomas). Pituitary
Magnetic Resonance Imaging (MRI) is essentialinprolactinoma (macroprolactinomas or macroprolactinomas). The
prolactin assay is performed by the electrochemiluminescent
immunometric method.
Dynamic Hormonal Investigations
Stimulation Test withGnRH
In the past, the GnRH test was used in the differential diagnosis of hypogonadotropic hypogonadism, but it is currently
no longer recommended because the assessment of testosterone and gonadotropins is sufcient to make the diagnosis.
The functional test of stimulation with GnRH, measuring LH
levels basal, 30 and 60minutes after intravenous administration of 100μg of GnRH, is used in the differential diagnosis
of delayed puberty. An LH concentration >10IU/L, 30minutes after GnRH administration, allows the diagnosis of constitutional pubertal delay. Functional testing is helpful in
patients preparing for pituitary surgery or with lesions in the
hypothalamic-pituitary region.
Human Chorionic Gonadotropin Stimulation Test
Like LH, human chorionic gonadotropin (hCG) stimulates
testosterone synthesis in Leydig cells. The hCG stimulation
test is recommended to assess Leydig cell function, especially in young men with congenital anorchidism (an autosomal recessive syndrome with male karyotype and variable
phenotype in the absence of testicular tissue) and to differentiate this clinical condition from cryptorchidism (failure of
Hypogonadism
The diagnosis of hypogonadism is essentially based on clinical signs and serum gonadotropin and testosterone levels measurement. The physical examination aim to
identifymorphological and structural alterations, with particular reference to skeletal proportions, height, weight, body
fat distribution, and gynecomastia. The urogenital examination is of primary importance in evaluating the degree of
development of secondary sexual characteristics.
Basal serum total testosterone isthe recommended diagnostic test for hypogonadism. A second blood draw should
conrm low total testosterone concentrations.
Numerous clinical and physiologic conditions mayalter
SHBG levels and, consequently, testosterone levels. Thus,
evaluating this SHBG is recommended in certain patients
(Table25.30).
Free or bioavailable testosterone assay is recommended
only when altered SHBG concentrations are suspected.
Several variables such as intra-individual testosterone uctuations, biological variability of the hormone’s action on
target organs, and limitations in currently available analytical techniques must be considered when assessing testosterone levels.
The combination of these factors has led to the lack of a
standardized cut-off that can distinguish eugonadal and
hypogonadal subjects; in this context, it is essential to integrate laboratory data with the clinical signs.
Gonadotropin evaluation provides helpful information
about the origin of testicular dysfunction and helps in the
differential diagnosis between primary and secondary
hypogonadism.
The nding of low testosterone concentrations with elevated FSH and LH blood values suggests primary hypogonadism (Fig.25.30). Karyotype analysis should be requested
in the case of suspected Klinefelter syndrome, and further
instrumental investigations help identify the cause. Elevated
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Clinical signs and symptoms of hypogonadism
Total testosterone dosage
Total testosterone
<reference cut-off*
Reassessment on second sample
of Free testosterone if changes in
[SHBG] are suspected
Total Testosterone on second
sample <reference cut-off*
Testosterone
free <reference cut-off*
FSH and LH assay
Elevated FSH
and LH levels
Diagnosis of
primary hypogo-
nadism
Further testing to
understand the cause:
• Iron metabolism
• Karyotype (to exclude
Klinefelter syndrome)
Fig. 25.30 Algorithm for the differential diagnosis of primary and secondary hypogonadism. *The values depend on the analytical methods
used. (Copyright EDISES 2021. Reproduced with permission)
Low or inappropriately normal
FSH and LH levels
Diagnosis of secondary
hypogonadism
Further testing to under-
stand the cause:
• Prolactin dosage
• Iron metabolism
• Pituitary Hormones
• MR
• Exclude use of opiates
and glucocorticoids
Normal
Total Testosterone
Hypogonadism
unlikely
FSH values with normal LH and testosterone levels indicate
impaired spermatogenesis with normal Leydig cell function.
Low or inappropriately normal gonadotropin concentrations
with below-normal testosterone values may suggest a secondary form (hypogonadotropic hypogonadism). In this
case, further investigations, such as serum prolactin levels,
transferrin saturation and pituitary hormones, MRI of the
sella turcica; drug treatment with glucocorticoidsare recommended. Excluding pathologies leading to secondary hypogonadism, idiopathic hypogonadotropic hypogonadism, or
genetically determined hypogonadotropic hypogonadism
should be considered, the latter recognizable through the
study of the phenotype (Kallmann syndrome, X chromosome deletions, etc.).
The different clinical forms of hypogonadism require different therapeutic approaches; therefore, a correct and accurate differential diagnosis is essential.Moreover, it should be
borne in mind that treatment is not always able to restore the
functions compromised in hormonal decompensation. For
subjects with primary hypogonadism, for example, hormone
therapy cannot restore fertility because the seminiferous
tubules are irreparably compromised. Furthermore, fertility
in subjects with secondary hypogonadism is often restored
by pulsatile GnRH therapy and gonadotropin therapy. When
hypogonadism is diagnosed, testosterone replacement therapy can provide benets in various psychophysical settings.
The treatment can prevent or improve osteopenia, slowing
down muscle mass loss, vasomotor instability, loss of libido,
and erectile dysfunction. Testosterone replacement therapy
is also contraindicated in individuals with prostate neoplasia
or breast cancer. There are different pharmacological formulations of testosterone (intramuscular, oral, transdermal, gel
formulation, subcutaneous implant).
Germ Cell Tumors oftheTestis
Germ cell tumors represent a very heterogeneous group of
diseases in terms of age of onset and clinical presentation,
with a generally favorable prognosis. A distinction is made
between gonadal (testicular or ovarian) and extra-gonadal
(sacrococcygeal region, retroperitoneum, and mediastinum)
tumors. In particular, testicular tumors, although very rare
(1% of all male cancers), represent the most common malignancy in men aged 15–44years in industrialized countries.
Approximately 98% of testicular neoplasms are germ cell
tumors; the remaining 2% includes Leydig cell tumors,
Sertoli cell tumors, rhabdomyosarcoma, and lymphoma. The
etiologic factors are not known. However, it is recognized
that subjects with retained testes (cryptorchidism) and dysgenetic gonads (e.g., Turner syndrome, Klinefelter syndrome, hermaphroditism) are predisposed to develop germ
cell tumors. Testicular germ cell tumors result from transforming germ cells, which arrests their maturation process.
The pluripotency of germ cell tumors manifests itself in different histological types: undifferentiated germ cells (seminoma), embryonal carcinoma, embryonal-like differentiated
cells (teratoma), extraembryonic differentiated phenotypes
(choriocarcinoma). Most testicular tumors are clinically
diagnosable at onset and present with a non-painful testicular mass, diffuse testicular pain, swelling, and induration.
Abdominal ultrasound and CT scan of the chest and abdo-
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Corpus luteum
Medullary
Pr
Interstitial
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men by the study of the retroperitoneum represent helpful
diagnostic tests. Biomarkers, such as α-fetoprotein (αFP),
β-chorionic gonadotropin (βhCG), and lactate dehydrogenase, are recommended for the diagnosis, staging of the disease, monitoring of therapy, and identication of recurrent
forms of the tumor. αFP is a glycoprotein typically produced
in the fetus and liver. Its circulating levels increase in different pathological conditions.
βhCG is a glycoprotein produced by syncytiotrophoblastic cells and consists of two subunits, α and β. The α
subunit is common to other pituitary hormones (FSH, LH,
TSH). The β subunit is specic and distinguishes it enzymatically and immunologically. βhCG is highly specic
for testicular cancer and is produced specically by choriocarcinoma cells. However, it can be detected in 5–10%
of pure seminomas. Lactate dehydrogenase is a less specic marker whose increase reects cell growth and proliferation rate. Increased plasma levels are observed in
approximately 80% of advanced seminomas. These markers should be evaluated cautiously, and false positives due
to physiological conditions, presence of other malignancies, or benign diseases should be considered. The persistence of elevated marker values at post-surgical follow-up,
after they have been restored within the reference ranges,
indicates occult metastases. The neoplasm, generally conned to the organ of origin, tends to disseminate via the
lymphatic route, leading to lymph node metastases (especially in germinomatous forms), and via the blood, leading
to mainly pulmonary metastases (especially in non-germinomatous forms).
Teratomas generally do not disseminate. Surgery represents the rst therapeutic approach. In the case of testicular
cancer, orchidectomy by inguinotomy is always indicated.
The prognosis of germ cell tumors is generally favorable,
even in situations with metastatic localization.
M. Ciaccio et al.
Secondary
follicle
imary
follicle
Fig. 25.31 Schematic representation of the ovary in childbearing age.
(Copyright EDISES 2021. Reproduced with permission)
Te rtiary
follicle
Mature
follicle
cells
Cortical
which ovarian follicles at various stages of maturation and
interstitial cells synthesing steroid hormones are found, and
an inner region, termed medullary, which is richly innervated
and vascularized and in which interstitial cells are less represented (Fig.25.31).
In the ovary, there is a morpho-functional unit called
ovarian follicle, which can perform gametogenic and endocrineovary functions. The gametogenic function consists in
the production of the female gamete, i.e., the mature ovum.
The endocrine function consists in hormones synthesis
(mainly progesterone, estrogen, and testosterone), which
determine the development of secondary sexual characteristics and the morphological and functional changes of the
female reproductive system necessary for theovum fertilization and implantation.
Ovary
MarcelloCiaccio and LuisaAgnello
Anatomy
The female gonads are two symmetrical oval-shaped organs.
They have an intraperitoneal location between the external
and internal iliac arteries. The size of the ovary of a woman
of childbearing age is approximately 2.5–5 cm in length,
1.5–3 cm in width, and 0.6–1.5 cm in thickness, but may
decrease during menopause. Histologically, a distinction can
be made between a peripheral region, termed cortical, in
Physiology
Female Hypothalamic-Pituitary-Gonadal Axis
The ovary performs the gametogenic function during the
ovarian cycle, which is temporally dened by the interval
between one ovulation and the next and lasts on average
28days. Given the difculty in clinically identifying ovulation, we prefer to talk about the menstrual cycle, i.e., the
period between one menstruation and the next. The menstrual cycle consists of a follicular phase, during which the
follicle matures until ovulation, which occurs approximately
halfway through the cycle, and a lutein phase, during which
the follicle is transformed into the corpus luteum, which in
turn is destined to degenerate in the absence of conception
and implantation. In parallel with the follicle'stransforma-
FSH
LDL
Theca cell
Granulosa cell
GnRH
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+
Hypothalamus
Hypophysis
369
inhibin A in maintaining low FSH and LH levels. The lack of
gonadotropin stimulation will lead the corpus luteum to pro-
–
gressive degeneration and reduced estradiol synthesis in the
late lutein phase. Consequently, as the negative feedback
exerted by estradiol at the hypothalamic level on the release
of GnRH is eliminated, the synthesis of FSH resumes, giving
rise to a new cycle.
FSH
+
LH
Ovary
Fig. 25.32 Hypothalamic-pituitary regulation of ovarian hormone
synthesis. (Copyright EDISES 2021. Reproduced with permission)
++–
Estradiol
Inhibin
Activin
–
profound morphological changes that adapt to the fertilized
ovum’s implantation.
Overall, the ovarygametogenic function is regulated by a
complex hormonalsystem consisting of the hypothalamicpituitary axis and the related positive and negative feedback
systems induced by ovarian hormones (Fig.25.32).
Gonadotropins (FSH and LH) are secreted by pituitary
gonadotropic cells in response to hypothalamic
GnRH.During the follicular phase, there is a moderateFSH
increase, which starts already in the late lutein phase of the
previous cycle. FSH determines the selection of the dominant follicle, which manifests rapid growth capacity. In this
phase, FSH, the predominant circulating gonadotropin,
interacts with the receptors of the follicle’s granulosa cells,
inducing aromatase activity, followed by a massive production of estrogen. The progressive increase in circulating
estradiol culminates with a peak around day 12 of the cycle,
i.e., in the late follicular phase. Estradiol acts at the pituitary
level by inducing the release of gonadotropins, especially
LH, with a typical positive feedback mechanism. As soon as
LH reaches discrete concentrations in the circulation, its
inhibitory activity on the enzyme 17α-hydroxylase expressed
in the interstitial cells of the theca of the follicle is manifested, thus, inhibiting the synthesis of androstenedione and
consequently of estradiol, which in the ovulatory phase
returns to low levels. The pre-ovulatory peak of circulating
gonadotropins determines the maturation of the follicle leading to ovulation. At the beginning of the lutein phase, when
the concentration of estradiol has decreased, the positive
feedback exerted on the hypothalamus is also lost, and therefore the release of gonadotropins. Therefore, their concentrations return to pre-ovulatory levels. The lutein phase is
characterized by a progressive increase in circulating levels
of progesterone, whose synthesis is supported by theca
luteincells. This hormone acts in synergy with estradiol and
Synthesis andFunctions ofSteroid Hormones
The ovary produces estradiol, progesterone, and androstenedione, from which testosterone is derived.
The ovary’s key feature of steroid biosynthesis is its compartmentalization into highly specialized cells. According to
the bicellular steroidogenesis model, the interstitial cells of
the theca of the follicle are sensitive to LH’s action due to
specic receptors. LH in these cells induces the synthesis of
androgens, which, in the granulosa cells sensitive to the FSH
action, will be converted into estrogens by aromatase activity. It should be noted that granulosa cells cannot synthesize
androgens (Fig.25.33).
The biosynthesis of steroid hormones occurs through the
activity of enzymes belonging to the cytochrome P450
superfamily. The precursor common to all biosynthetic pathways is cholesterol, mainly derived from LDL lipoproteins
and, to a negligible extent, from ex novo biosynthesis and
mobilization of cytoplasmic lipid deposits.
The limiting step in steroid hormone synthesis is cholesterol transport within the mitochondrion. Once localized in
the inner mitochondrial membrane, cholesterol is converted
R-LH R-LDL
LH
DHT
R-FSH
Aromatase Aromatase
Estrone
Fig. 25.33 Ovarian steroidogenesis. (Copyright EDISES 2021.
Reproduced with permission)
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M. Ciaccio et al.
Cholesterol
mainly to the control of LH. This hormone induces in the
theca cells the expression of P450scc (human cholesterol
Pregnenolone
side-chain cleavage enzyme), the enzyme converting cholesterol into pregnenolone, considered the limiting step of the
entire biosynthetic pathway. Although not directly acting on
17-OH-pregnenolone
Progesterone
the ex novo biosynthetic pathway, FSH has a critical regula-
tory role in converting androgens to estradiol by inducing the
expression of aromatase in granulosa cells (Fig.25.33).
DHEA
17-OH-progesterone
vector proteins such as SHBG (Sex Hormone Binding
Globulin), which binds estrogens and androgens,
Androstenedione
corticosteroid- binding globulin, which mainly binds progesterone, and albumin, which is considered an aspecic trans-
Testosterone
Estrone
porter. The synthesis of these transport proteins occurs in the
liver and is also modulated by insulin. Both estrogen and
progesterone are catabolized in the liver.
Estriol
Fig. 25.34 Pathways of synthesis of androgens and estrogens. In the
ovary, the Δ4 pathway is prevalent compared to Δ5, which occurs
mainly in the adrenal gland. (Copyright EDISES 2021. Reproduced
with permission)
interaction with nuclear receptors expressed in target cells,
followed by modulation of gene expression. The biological
effects of estrogens are ubiquitous. During puberty, they play
a decisive role in developing the internal and external genitalia and in the induction of secondary sexual characteristics.
In the fertile age, they are involved in fertilization, preg-
to pregnenolone. This can follow two metabolic pathways,
depending on cellular localization (Fig.25.34). The Δ4 pathway represents the main pregnenolone metabolizationpathway in the ovary and leads to the formation of progesterone.
nancy, and childbirth. Estrogens also affect lipid metabolism
by regulatingthe PCSK9expression in the liver. However,
many aspects of the action of estrogen (endogenous or exogenous) on lipoprotein metabolism remain unclear.
In interstitial cells, including those in the corpus luteum,
pregnenolone is converted to progesterone and
17-OH-progesterone by a 17α-hydroxylase. The progressive
removal of carbon atoms from progesterone (C21) leads to
the C19-androgens synthesis, particularly
Δ4-androstenedione. Hilar cells of the ovary can con-
Synthesis andFunction ofProtein Hormones
In addition to steroid hormones, the ovary synthesizes peptides with regulatory action on ovarian function. Inhibins A
and B, Anti-Müllerian Hormone (AMH), and activins belong
to this class.
vert Δ4-androstenedione to testosterone. The
Δ5-metabolization pathway occurs mainly in the adrenal
gland and involves the conversion of pregnenolone to
17-OH-pregnenolone and dehydroandrosterone, which is
then converted to androstenedione and testosterone. Estrogen
synthesis occurs almost exclusively in the ovary and, to a
lesser extent, in the adrenal gland. Estradiol, the primary
estrogen synthesized by the ovary, and estrone are derived
from Δ4-androstenedione and testosterone by aromatase
expressed mainly in the granulosa cells.
Another important pathway for testosterone metabolism
involves dihydrotestosterone synthesis by the 5α-reductase.
This conversion also takes place in the ovary, especially
medullary interstitial cells, and other districts, such as the
skinin the pilosebaceous unit, which has the enzymatic kit
for the synthesis and metabolism of androgens; in particular,
licular uid as peptides capable of inhibiting pituitary FSH
secretion. Two isoforms were identied, inhibin A and B,
belonging to the TGF-β superfamily. Inhibins regulate ovarian function locally, through paracrine mechanisms, or by
inhibiting pituitary FSH release. Inhibins act as antagonists
of activins, constituting a structural homolog. The active
form of the inhibins is a heterodimer consisting of an exclusive α subunit and a β subunit, shared with the activins, of
which there are two isoforms, A and B.The combination of
these subunits gives rise to inhibin A (α/βA) and inhibin B
(α/βB). Given the structural homology with activins, inhibins bind to the pituitary receptor and, through the betaglycans, considere co-receptors,on the cell surface, inhibit the
access of activins to the receptor, blocking the intracellular
signal transduction pathway.
it expresses the 5α-reductase, necessary for the conversion of
testosterone into DHT (dihydrotestosterone, DHT).
mature follicles, while inhibin A is expressed by granulosa
The ex novo synthesis of ovarian hormones responds
Ovarian hormones are transported in the circulation by
The actions of estrogen and progesterone are mediated by
Inhibins were rst isolated in the late 1980s from the fol-
Inhibin B is mainly produced by the granulosa cells of
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and theca cells. Circulating levels of the two molecules vary
physiologically as a function of the ovarian cycle: inhibin B
increases in response to FSH, increasing in the follicular and
ovulatory phases, while inhibin A peaks in the lutein phase.
Activins act oppositely to inhibins by stimulating the pituitary release of FSH and inducing the action of FSHdependent aromatase.
AMH is a glycoprotein also belonging to the TGF-β
superfamily. Its function has long been known in relation to
its ability to direct sexual differentiation during the early
stages of embryonic development. AMH is synthesized primarily by antral follicles. It has been proposed that AMH
acts by inhibiting follicle sensitivity to FSH and may play a
role in the process of dominant follicle selection. In the early
stages of follicle development, AMH synthesis is high, inhibiting the recruitment of non-dominant follicles by paracrine
mechanisms. As soon as the antral follicle increases in size,
AMH synthesis rapidly decreases, making the follicle susceptible to the action of FSH and ensuring its subsequent
development.
Given their biological actions, Inhibin B and AMH have
now been considered ovarian reserve markers, together with
FSH and estradiol assays.
Endocrine Disorders oftheOvary
Hirsutism andVirilization
Hirsutism is dened as excessive hair growth with male distribution in women. The leading causes of hirsutism are
described in Table25.31. Often, hirsutism is an expression of
hyperandrogenism, of which it is the most frequent clinical
sign. Sometimes, however, it can also be idiopathic and not
associated with increased circulating androgens. On the
other hand, it should also be mentioned that the absence of
hirsutism does not exclude other conditions associated with
androgen excesses, such as acne, alopecia, anovulatory
cycles, or dysmenorrhea. The marked increase in circulating
androgens may be accompanied by virilization, a rare condition dened by the progressive regression of female sexual
characteristics and the appearance of male characteristics.
Virilization manifests by clitoral hypertrophy, breast atrophy, increased muscle mass, changes in voice tone, and
amenorrhea.
Testosterone and dihydrotestosterone bind to the androgen receptor. DHEA, DHEA-S, and androstenedione are
prohormones. Given the peripheral synthesis of DHT, it
should be noted that the circulating concentration of androgens may not reect the actual concentration of active hormone in the pilosebaceous unit. Moreover, the local effect of
androgens depends on specic receptors, whose expression
is not yet dened either in terms of localization in the pilose-
Table 25.31 Main causes of primary amenorrhea
Without sexual maturation
Ovarian causes (hypergonadotropic hypogonadism)
- Congenital ovarian dysgenesis
- Turner syndrome
- 17α-hydroxylase deciency
- Mutations of ovarian receptors for gonadotropins
Hypothalamus/pituitary causes (hypogonadotropic
hypogonadism)
- Functional hypothalamic amenorrhea
- Pituitary adenomas
- Head radiation therapy
- Head trauma
- Neurosurgery
- Inammatory/inltrative diseases
- Congenital GnRH deciency (Kallman syndrome)
Constitutional delayed puberty
With sexual maturation
Congenital changes in the genital development
- Dysgenesis of the Müllerian ducts
- Androgen insensitivity syndrome
- Imperforate hymen
- Vaginal septum
- Stenosis of the cervix
baceous unit or body distribution. Hirsutism, therefore,
results from the complex interactions between the circulating levels of androgens, their local bioavailability, and the
sensitivity of the target cells. This explains the poor correlation between circulating levels of androgens and hirsutism.
Amenorrhea
Amenorrhea is dened as the absence of spontaneous menstrual cycles. It can be distinguished into primary amenorrhea when no menstrual cycles occur by age 16, and
secondary or oligorrhea, when no menstrual cycles occur for
at least 3 months in women with previous regular
menstruation.
Primary Amenorrhea
Primary amenorrhea is a rare condition in about 1% of the
female population and can occur in the absence or presence
of sexual maturation. In the rst case, the causes of amenorrhea should be investigated as early as 13years. Primary
amenorrhea can result from an alteration in the ovary, the
hypothalamus, or the pituitary gland (Table25.32).
Primary or hypergonadotropic hypogonadism is characterized by high circulating levels of gonadotropins. In ovarian failure, the negative feedback control on the hypothalamus
is lost, resulting in an uncontrolled release of FSH and
LH. Hypergonadotropic hypogonadism can be caused by
congenital ovarian dysgenesis, Turner syndrome, deciency
of enzymatic activities involved in steroidogeneses, such as
17α-hydroxylase deciency, or mutations in FSH or LH
receptors causing ovarian resistance to gonadotropins.
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