22 Chapter

Outline
The Testes
Gonadal Function Functional Anatomy of the Male Reproductive Tract
Physiology of the Testicles
Disorders of Sexual Development and Testicular Hypofunction
MAHIMA GULATI
Diagnosis of Hypogonadism
Testosterone Replacement Therapy
Monitoring Testosterone Replacement Therapy
The Ovaries
Early Ovarian Development
Functional Anatomy of the Ovaries
Hormonal Production by the Ovaries
The Menstrual Cycle
Hormonal Control of Ovulation
Pubertal Development in the Female
Precocious Sexual Development
Menstrual Cycle Abnormalities
Hirsutism
Estrogen Replacement Therapy
Questions
References
Chapter Objectives
Upon completion of this chapter, the clinical laboratorian should be able to do the following:

Discuss the biosynthesis, secretion, transport, and action of the sex steroids and gonadotropins.
Identify the location of the pituitary, ovaries, and testes.
Describe the hypothalamic–pituitary–ovarian and hypothalamic–pituitary–testicular axes and
how they regulate sex steroid and gonadotropin hormone production.
Explain the principles of each diagnostic test for pituitary–gonadal axes dysfunction.
Correlate laboratory information with regard to suspected gonadal disorders, given a patient's
clinical data.
Describe the appropriate laboratory testing protocol to effectively evaluate or monitor patients
with suspected gonadal disease.
 Key Terms thickenings in the ridges indicate the developing genital ducts and the
Amenorrhea
mesonephric (formerly called wolffian) and paramesonephric (formerly called
Androgen müllerian) ducts. In the male, the Leydig cells of the fetal testes produce
Corpus luteum androgen, which stimulates the mesonephric ducts to form the male genital ducts
Follicle-stimulating hormone (ductus deferens, epididymis, seminal vesicles, and ejaculatory ducts), and the
Follicular phase Sertoli cells produce a hormone that suppresses formation of the
Graafian follicle paramesonephric ducts (antimüllerian hormone [AMH]). In the female (or in an
Gynecomastia
Hirsutism
embryo with no gonads), the mesonephric ducts regress, and the
Hypogonadism paramesonephric ducts develop into the female duct system. In the early embryo,
Inhibin the external genitalia consist of a genital tubercle, paired labioscrotal swellings,
Leydig cells and paired urethral folds. From this undifferentiated state, male external genitalia
Luteal phase develop under the influence of androgens or, in the absence of a testis, female
Luteinizing hormone external genitalia are formed regardless of whether an ovary is present.
Ovulation
Sertoli cells There are three important steps in sexual differentiation and the development
Virilization of the normal male phenotype. The first is the differentiation of bipotential
gonad primordia (identical in both XX and XY fetuses) into the testes that
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secrete testosterone, which is under the control of the SRY protein coded by that
Y chromosome gene. The second is the development of the internal reproductive
tract, initiated by fetal testicular androgen production. In male fetuses, this
THE TESTES requires the presence of AMH that causes involution of the müllerian ducts, the
anlage for the female type reproductive tract. The third is the development of the
By the 6th week of development in both sexes, the primordial germ cells have external genitalia that requires testosterone and, in some target tissues, its more
migrated from their extraembryonic location to the gonadal ridges, where they potent metabolite 5α-dihydrotestosterone (DHT).
are surrounded by the sex cords to form a pair of primitive gonads. Whether Several genes are important for normal gonadal differentiation (and their
chromosomally 46 XX or 46 XY, the developing gonad at this stage of mutations may lead to disorders of sexual differentiation). Steroidogenic factor 1
development is bipotential.
(SF-1)1 is important for differentiation and maintenance of both gonadal and
The ovarian pathway is followed unless a gene on the short arm of the Y adrenal tissue, increasing the synthesis of testosterone and reducing its
chromosome, designated TDF (testis-determined factor) also known as sex- conversion to estradiol via the transcriptional regulation of the hydroxylases and
determining region Y (SRY) gene, makes a DNA-binding protein that acts as a P450 aromatase, respectively. It may also regulate transcription of the AMH2
switch, diverting development into the male pathway. In the presence of the Y gene in synergy with WT1.3 Testicular descent is regulated by the protein
chromosome (and due to the SRY protein), the medullary tissue starts forming product of gene Insl3, which is a member of the insulin-like family and is
typical testes with seminiferous tubules and Leydig cells by 7 weeks of secreted by Leydig cells. Insl3 seems to be important in gubernaculum
gestation. Leydig cells under the stimulation of human chorionic gonadotropin formation, and mutations in its gene have been shown to be linked with bilateral
(hCG) from the placenta become capable of androgen secretion by week 10. The cryptorchidism in male mice,4 and in addition, Insl3 protein may also be a
spermatogonia, derived from the primordial germ cells by 200 or more biomarker for Leydig cell function. Insl3 also seems to play a role in female
successive mitoses, form the walls of the seminiferous tubules together with fertility (see below).
supporting Sertoli cells.
While the primordial germ cells are migrating to the genital ridges, Functional Anatomy of the Male Reproductive Tract
Adult testes are paired, ovoid organs that hang from the inguinal canal by the
spermatic cord, which comprises a neurovascular pedicle, vas deferens, and
cremasteric muscle. The testes are located outside the body, encased by a
muscular sac. Blood flow is governed by an intricate plexus of arterial and
venous blood flow that, together with contraction of the dartos muscle in the
scrotal sac, regulates the temperature of the testicles to 2°C below core body
temperature. This important function is vital to uninterrupted sperm production.
Also encased in the muscular sheath is the spermatic cord, which has the ability
to retract the testicles into the inguinal canal in instances of threatened injury.
The testes themselves are comprised of two anatomical units: a network of
tubules, known as the seminiferous tubules, and an interstitium. The tubules
contain germ cells and Sertoli cells and are responsible for sperm production.
The testes serve dual functions, which include (1) production of sperm and (2)
production of reproductive steroid hormones.5 In the embryonic stage, the
dominant male sex hormone, testosterone (T), aids in development and
differentiation of the primordial gonads.
Puberty marks the transition from a nonreproductive state into a reproductive
state and is associated with adrenarche with increase in adrenal androgen and
gonadarche. Tanner staging of the pubertal and axillary hair changes and
genitalia is used in children to mark pubertal changes, which are characterized
by growth spurt, increased muscle mass, psychological changes, and male
pattern hair growth. The earliest sign of puberty in boys is testicular enlargement
that results from rising luteinizing hormone (LH) and follicle-stimulating
hormone (FSH). After puberty, throughout adulthood, and until late in old age,
testosterone helps with sperm production and maintains secondary sexual
characteristics.
The sperm move sequentially through the tubuli recti; rete testes; ductuli
efferentes testes; the head, body, and tail of the epididymis; and, finally, into the
vas deferens. Various secretory products of the seminal vesicles and prostate mix
with sperm to form the final product: semen. Seminal vesicle secretions are rich
in vitamin C and fructose, important for the preservation of motility of the
sperm.
Physiology of the Testicles
Spermatogenesis
Sperm are formed from stem cells called spermatogonia. The spermatogonia
undergo mitosis and meiosis; finally, the haploid cells transform to form mature
sperm. The mature sperm has a head, body, and tail, which enables it to swim for
the purpose of forming a zygote with the haploid ovum. Certain spermatogonia
stagger division so that sperm production is uninterrupted and continuous. The
Sertoli cells are polyfunctional cells that aid in the development and maturation
of sperm.6
Hormonogenesis
Testosterone, the predominant hormone secreted by the testes, is controlled
primarily by two pituitary hormones: FSH and LH.7 Because these hormones
were first described in women, they are named in reference to the menstrual
cycle. Both hormones are produced by a single group of cells in the pituitary
called gonadotrophs. FSH acts primarily on germinal stem cells8 and LH acts
primarily on the Leydig cells7—located in the testicular interstitium—that
synthesize testosterone. Gonadotropins (LH and FSH) are glycoproteins and
share an alpha subunit with thyroid-stimulating hormone (TSH) and hCG. The
beta subunit confers biological specificity for them.
Hormonal Control of Testicular Function
The hypothalamus, located in the brain, generates a hormone called
gonadotropin-releasing hormone (GnRH) in a pulsatile fashion. GnRH is
synthesized in neurons situated in the arcuate nucleus and other nuclei of the
hypothalamus and is released into the portal hypophyseal system that, in turn,
determines the production of LH and FSH from the pituitary gland. Impaired
pulse generation of GnRH leads to inadequate production of LH and FSH,
resulting in hypogonadism.9 The first, and rate-limiting, step in the testicular
steroidogenesis is the conversion of cholesterol to pregnenolone. This
cholesterol is either trapped by endocytosis from the blood lipoproteins or
synthesized within the Leydig cells. The LH binds to the glycoprotein receptor
in the cell wall and induces intracellular cyclic AMP production that, in turn,
activates protein kinase A, which catalyzes protein phosphorylation. This latter
step induces testosterone synthesis. The testicular steroidogenesis pathway is
similar to the pathway in the adrenal cortex and they share the same enzymatic
systems. Testosterone is the principal androgen hormone in the blood, and after
puberty, the testes secrete 4 to 10 mg daily and less than 5% is derived from
adrenal precursors such as dehydroepiandrosterone (DHEA) and
androstenedione. It is largely bound, with 2% to 3% free. About 50% of
testosterone is bound to albumin and about 45% is bound to sex hormone–
binding globulin (SHBG). The concentration of binding protein determines the
level of total testosterone but not the free testosterone levels during laboratory
estimation. Testosterone and inhibin are the two hormones secreted by the testes
that provide feedback control to the hypothalamus and pituitary. Leydig cell
steroidogenesis of testosterone is primarily controlled by LH secretion, with
negative feedback of testosterone and estradiol on the hypothalamic–pituitary
axis. FSH acts on Sertoli cells to stimulate protein synthesis, inhibin, and
androgen-binding protein. The actions of both testosterone and FSH on Sertoli
cells are synergistic, permitting completion of spermatogenesis. FSH stimulates
production of an androgen receptor that makes the Sertoli cell responsive to
androgen and, in turn, androgens stimulate synthesis of FSH receptors. Feedback
on FSH is attributed to inhibin.10
Testosterone concentration fluctuates in a circadian fashion, reflecting the
parallel rhythms of LH and FSH levels. This fact should be considered when
interpreting serum levels of testosterone: the highest level is found at about 6 AM
and correlates with most laboratory normal ranges, and the lowest level is found
at about 12 AM (in a male with a normal sleep–wake cycle).
Cellular Mechanism of Testosterone Action
Testosterone enters the cell and converts to DHT in cells rich in 5α-reductase,
such as some hair follicles and prostate. DHT and testosterone complex with an
intracellular receptor protein and this complex bind to the nuclear receptor,
effecting protein synthesis and cell growth.
Physiologic Actions of Testosterone
Prenatal Development
this gap in stimulation of testosterone production by the fetal testes. Exposure of
testosterone to the Wolffian duct leads to differentiation of the various
components of the male genital tract. Sertoli cells produce AMH, which aids in
regression of the female primordial genital tract. The scrotal skin is rich in 5α-
reductase, which converts testosterone to DHT. Fetal exposure to drugs that
block this enzyme and DHT formation leads to feminization of the genitalia of
the male fetus.
Postnatal Development
Testicular function is reactivated during puberty after a period of quiescence to
produce testosterone that results in development of secondary sex hair (face,
chest, axilla, and pubis), enhanced linear skeletal growth, development of
internal and external genitalia, increased upper body musculature, and
development of larynx and vocal cords with deepening of the voice.11, 12, 13
Possible mood changes and aggression are undesired effects that may occur
during puberty. The linear growth effects of testosterone are finite, with
epiphyseal closure when genetically determined height is achieved.
Hypogonadism during puberty leads to imprecise closure of growth plates,
leading to excessive height, long limbs, and disproportionate upper and lower
body segments. Male secondary sexual characteristics can be staged by a system
of development devised by Marshall and Tanner (Table 22.1).
TABLE 22.1 Tanner Staging of Genital and Pubic Hair Development in
Males

Early in development, embryos have primordial components of the genital tracts

of both sexes. The primitive gonads become distinguishable at about the 7th
week of embryonic stage. Both chorionic gonadotropins and fetal LH stimulate
production of testosterone by the fetal Leydig cells. In the fetus, the
hypothalamo-hypophyseal vascular connections are responsible for LH release
by hypothalamic GnRH and are established between 11 and 12 weeks after
conception, which is 3 weeks after testosterone production by the Leydig cells of
the testis. hCG, which has LH-like action, made by the placenta, accounts for
 (temporal hairline recession). Failure to develop secondary sexual characteristics
should prompt evaluation for hypogonadism or constitutional delay in boys.
Loss of secondary sexual characteristics might occur gradually and should
prompt evaluation for hypogonadism because, among other effects, low
testosterone levels lead to loss of bone mass and development of osteoporosis in
males at any age.

Disorders of Sexual Development and Testicular

Hypofunction
Pubertal development could be premature (precocious) or delayed, even if
development is normal at birth.14,15 Precocious sexual development results from
the premature exposure of sex steroids, which might arise from early
gonadotropin secretion or production by the adrenal glands or testes. Detailed
descriptions of the sequence of hormonal pubertal abnormalities of hair, genitals,
and breasts are beyond the scope of this text. The differential diagnosis of
hypogonadism includes a diverse group of disorders affecting the testicles and
the hypothalamic–pituitary regulation of the testes outlined in Box 22.1. Certain
important disorders are explained in the following section.

BOX 22.1 Causes of Delayed Puberty

Delayed puberty or hypogonadism, with increased gonadotropins
Effect on Spermatogenesis (FSH and/or LH)
Klinefelter's syndrome
Stimulation of Leydig cells induces production of testosterone. Testosterone, Bilateral gonadal failure
acting with FSH, has paracrine effects on the seminiferous and Sertoli cells, Primary testicular failure
inducing spermatogenesis. Exogenous overuse or abuse of testosterone, such as Anorchia
Vanishing testicles
occurs with some athletes, will reduce the high intratesticular concentration of
testosterone, leading to reduction of sperm production. Chemotherapeutic agents
Irradiation
Trauma
Effect on Secondary Sexual Effects Infection (mumps orchitis)
Delayed puberty with normal or low FSH and/or LH
Testosterone has growth-promoting effects on various target tissues. The Constitutional delayed puberty16
secondary sex characteristics that develop during puberty are maintained into Hypothalamic dysfunction
late adulthood by testosterone.13 The prostate enlarges progressively during Malnutrition
adulthood, while exposure of scalp hair results in regression of the hair follicles Chronic systemic illness
 Severe obesity resulting in elevated estrogen levels. Men with Klinefelter's syndrome may have
Central nervous system tumors reduced bone density and breast cancer risk comparable to women.
Hypopituitarism
Panhypopituitarism Testicular Feminization Syndrome
Kallmann's syndrome (anosmia, cleft palate, and reduced FSH and LH
levels) Testicular feminization syndrome is the most severe form of androgen resistance
Isolated GH deficiency syndrome, resulting from mutations of the androgen receptor and impaired
Hyperprolactinemia (prolactinoma or drug induced) androgen actions in target tissues. As a result of the lack of androgen and
Hypothyroidism unopposed estrogen effects, the physical development pursues the female
Miscellaneous phenotype, with fully developed breast and female distribution of fat and hair.
Prader-Willi syndrome Most present for evaluation of primary amenorrhea, at which time the lack of
Laurence-Moon syndrome female internal genitalia becomes apparent. The testicles are often undescended,
LEOPARD syndrome and failure to promptly remove these organs is essential to abort malignant
Bloom syndrome transformation. Biochemical evaluation reveals normal or elevated serum
Germ cell neoplasia concentrations of testosterone with elevated FSH and LH levels. There is no
Male pseudohermaphroditism utility or response to administration of exogenous testosterone. They are reared
Ataxia–telangiectasia as girls. There is a wide variation in androgen insensitivity and in corresponding
Steroidogenic enzyme defects clinical deficits in male sexual development.

Hypergonadotropic Hypogonadism
Hypergonadotropic hypogonadism incorporates a group of disorders
characterized by low testosterone, elevated FSH or LH, and impaired sperm
production.
Klinefelter's Syndrome
Klinefelter's syndrome occurs in about 1 of 400 to 600 men and is caused by the
presence of an extra chromosome; in fact, it is the most common human sex
chromosome abnormality. The most common karyotype is 47, XXY.11. Men
with this disorder have small (<2.5 cm), firm testicles. Gynecomastia
(enlargement of the male breast) is commonly present at the time of diagnosis.
Due to reduced production of testosterone, LH levels are elevated. Due to
deficient seminiferous tubule mass, FSH is elevated from underproduction of
inhibin.17 These men also have azoospermia and resultant sterility. Men with
mosaicism may produce some sperm and pregnancies have been reported with
such men. Elevated levels of FSH and LH induce increased aromatase activity,
5a-Reductase Deficiency
Deficiency of 5α-reductase is a rare cause of androgen insensitivity and results
in a mutation encoding the type 2 isoenzyme, maps to chromosome 2p23, and is
expressed in XY males. A reduction in levels of the enzyme 5α-reductase results
in decreased DHT concentrations. Physical development is similar to the female
phenotype until puberty when the wolffian ducts virilize in response to
testosterone. The female internal genitalia are absent and the male internal
genitalia are well developed (epididymis, vas deferens, and seminal vesicle) in
response to testosterone. DHT is essential for the development of the prostate
and external genitalia during embryonic virilization.
Myotonic Dystrophy
Myotonic dystrophy (type 1 caused by DMPK gene mutation and type 2 caused
by CNBP gene mutation) is inherited in an autosomal dominant fashion (almost
always, an affected person has one parent with the condition) and presents with
primary hypogonadism, frontal balding, diabetes, and muscle weakness, atrophy,
and dystonia (an inability of the muscle to relax adequately after contraction).
The incidence of DM is 1 in 8,000 worldwide. Testicular failure typically
presents in the twenties and thirties; however, puberty progresses normally and
male secondary sexual characteristics, height, bone growth, etc., are attained
normally during pubertal course of development. Primary hypogonadism occurs
with primarily germ cell compartment failure (i.e., oligozoospermia and
infertility), with elevated serum FSH. In later stages, failure of Leydig cell
compartment resulting in low serum testosterone, elevated LH concentrations,
and testicular atrophy occurs. Testicular failure happens more commonly in
DM1 (type 1 myotonic dystrophy) than in DM2.
Testicular Injury and Infection
Mumps orchitis develops in a third of postpubertal males with mumps and is the
most frequent extrasalivary manifestation of this highly contagious infection.
Mumps epididymo-orchitis is usually unilateral (85% of the times); therefore,
permanent sterility is rare (contrary to popular belief). Most cases of orchitis
occur within 4 to 6 days of parotitis, but it may precede parotitis or be the only
manifestation of mumps. Intermittently, mumps outbreaks have been reported in
secondary schools, colleges, universities, and military groups; however, the
absolute numbers are still quite low at a few hundred cases reported in a year in
the United States. Other infectious causes of orchitis like TB, Chlamydia,
gonorrhea, etc., are fortunately rare in the United States. Radiation and
chemotherapy for cancer can result in long-term testicular damage.
Sertoli Cell–Only Syndrome
Sertoli cell–only syndrome (SCO syndrome or germ cell aplasia) is characterized
by a lack of germ cells. Men present with small testes, high FSH levels,
azoospermia, and normal testosterone levels. Testicular biopsy, which is
necessary for diagnosis, shows lack (or complete absence) of spermatozoa. This
disorder may arise from Y chromosome microdeletions on Yq11 locus (AZF
region: Azoospermia Factor). It is relatively rare, affecting 5% to 10% of all
infertile men in the country.
Hypogonadotropic Hypogonadism
The hallmark of disorders of hypogonadotropic hypogonadism is the occurrence
of low testosterone levels together with low or inappropriately normal FSH or
LH levels.
Kallmann's Syndrome
The impaired secretion of GnRH has been elucidated in the X-linked form of
congenital GnRH deficiency, which results from impaired migration of GnRH
neurons and olfactory nerves to the ventral hypothalamus during embryogenesis.
Proper migration of these neurons is dependent on the correct expression of
anosmin, a 680–amino acid neural cell adhesion molecule–like protein, which is
the product of the KAL1 gene.
Mutations in the KAL1 gene (a gene found on the X chromosome) occur less
often in sporadic cases (<10%). In general, the clinical phenotypes of idiopathic
hypogonadotropic hypogonadism (IHH) subjects with KAL1 mutations are
characterized with a high incidence of microphallus, cryptorchidism, and small
testes. X-linked KAL mutations have never been observed in families with
normosmic IHH (nIHH) or in families with both anosmic and nonanosmic
individuals.18,19
Kallmann's syndrome is a result of an inherited, X-linked recessive trait that
manifests as hypogonadism during puberty. The frequency of this syndrome is 1
of 10,000 males. Certain men also have red-green color blindness, congenital
deafness, or cerebellar dysfunction.
Hyperprolactinemia
Prolactin elevation resulting from any cause (drug-induced or prolactin-
producing tumors of the pituitary) can result in hypogonadotropic
hypogonadism20,21 due to impairment of both frequency and amplitude of FSH
and LH pulses, because of hypothalamic kisspeptin neuron–mediated disruption
of GnRH pulsatile secretion.22,23
Type 2 Diabetes
Type 2 diabetes is also associated with hypogonadotropic hypogonadism in at
least 25% to 50% of men.24 It is characterized by low free or total serum
concentrations of testosterone and inappropriately low LH.25 This may stem
from insulin resistance (insulin action seems to be important for LH release by
gonadotropes), low SHBG levels, inflammation (hypogonadism in type 2
diabetic males was seen to be associated with high C-reactive protein levels, an
inflammatory marker),24 and even elevated estradiol levels (due to testosterone
aromatization in adipose tissue). Of note, type 1 diabetes does not seem to be
associated with hypogonadism, provided glycemic control has remained good
and BMI is within normal limits.26
Age
There is a gradual reduction in testosterone after age 30, with an average decline
of about 110 ng/dL every decade. The Baltimore Longitudinal Study of Aging
revealed “hypogonadism” (reduced total testosterone concentrations) of 19% at
age 60, 28% at age 70, and 49% at age 80,27 with free testosterone
concentrations much lower in these men. Age is also associated with elevation of
SHBG by about 1%/year. Similar findings emerged from the Massachusetts
Male Aging Study, which showed 1.6%/year decline in total testosterone levels
and 2% to 3%/year decline in bioavailable testosterone (free and albumin-bound
testosterone) levels.28 Recently, the results of the Testosterone Trials were
published that showed significant improvement in sexual function in older men
greater than 65 years, given testosterone replacement for 1 year, but no
significant improvement in physical function or vitality.29
Pituitary Disease
Acquired hypogonadism can follow injury to the pituitary as a result of tumors,
surgical- or radiation-induced trauma, vascular injury, autoimmune hypophysitis,
or granulomatous or metastatic disease. Hemochromatosis is a rare cause of
pituitary dysfunction.
Opioid Use
Long-term or continuous use of narcotics has been linked to severe
hypogonadotropic hypogonadism (due to μ-opioid receptor–mediated decreased
GnRH pulsatile production) and even decrease in male fertility (decreased sperm
motility, decreased sperm counts, and abnormal sperm morphology).30
Obstructive Sleep Apnea
It is unclear if sleep apnea leads to hypogonadotropic hypogonadism (due to
hypoxemia and sleep deprivation),31 or if the obesity (which is often present in
men with sleep apnea) leads to decreased testosterone levels. It is to be noted
that testosterone replacement therapy (especially high-dose testosterone) may
worsen preexisting sleep apnea, possibly due to increased oxygen consumption;
and therefore, the Endocrine Society guidelines32 recommend not starting
testosterone replacement therapy in men with untreated severe OSA, until first
starting them on CPAP.
Diagnosis of Hypogonadism
Both clinical and biochemical features must be met (Fig. 22.1) to make the
diagnosis of hypogonadism. Testosterone concentrations have a circadian rhythm
and the time of sampling must be considered. Morning samples between 8 and
10 AM are recommended to match values from reference interval studies.
Multiple estimation of free and bound testosterone levels should be done on
different days before a diagnosis of testosterone deficiency is confirmed.32 The
distinction between primary (disease or destruction of the testes) versus
secondary (disease or destruction of the pituitary) or tertiary (hypothalamic) is
relatively easy to make. FSH and/or LH33 values are elevated in primary
hypogonadism and are inappropriately normal or low with secondary or tertiary
etiologies. Pituitary MRI should be done in secondary hypogonadism in young
individuals. Older individuals often have secondary or tertiary (hypothalamic)
dysfunction as a result of reduced hypothalamic pulse generator frequency,
resulting in low or inappropriately normal FSH and/or LH levels.34 Clinical
signs and symptoms of hypogonadism (e.g., loss of secondary sexual
characteristics, decreased muscle mass, osteoporosis, etc.) should be
corroborated with low testosterone levels, particularly when testosterone
replacement therapy is considered.32
 concentrations can be achieved satisfactorily whether the testosterone deficiency
is due to primary or secondary hypogonadism.
States are as follows:
FIGURE 22.1 Clinical diagnostic evaluation of male hypogonadism. PRL,
prolactin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; hCG,
human chorionic gonadotropin; GnRH, gonadotropin-releasing hormone.
Testosterone Replacement Therapy
The following principles should guide testosterone therapy: testosterone should
be administered only to a man who is hypogonadal, as evidenced by clinical
symptoms and signs consistent with androgen deficiency and a distinctly
subnormal serum testosterone concentration. Treating symptoms of
hypogonadism without corroborating biochemical evidence of testosterone
deficiency is not recommended. Restoring testosterone to midnormal
The currently available modes35 of testosterone administration in the United
1. Parenteral testosterone. This is the most widely available and cost-
effective mode of administration. The cypionate and enanthate esters of
testosterone are available for intramuscular injection. The peak level is
achieved in 72 hours and the effect lasts for a period of 1 to 2 weeks.
Weekly administration provides for a lower peak and less fluctuation within
the normal range of testosterone levels. Usual dosing is 50 to 100 mg
weekly or 150 to 250 mg once every 2 weeks. Testosterone dose should be
based on lean body mass, not on body weight, and is best reached by
administering a standard dose of testosterone, with minor dose escalations
based on serum testosterone levels measured midpoint between two
injections. The goal is to maintain this middose level at midpoint of the
normal ranges. Recently, FDA has approved extra-long-acting testosterone
undecanoate injection, which can be injected every 10 weeks (after the first
2 doses, which need to be injected in a 4-week interval), but this injection is
available only under AVEED REMS program,36 due to possible risk of
serious adverse effects of pulmonary oil microembolism (POME) and
anaphylaxis.
2. Transdermal testosterone patch therapy. This mode of administration
provides more physiologic levels of testosterone. The patch is permeability
enhanced to aid in the absorption of testosterone through normal skin. Local
skin irritation can occur and often limits the patch use.
3. Testosterone gel. This hydroalcoholic gel preparation is applied to
nongenital skin once daily. The absorption is gradual and provides blood
levels of testosterone in the normal range for 24 hours. The main concern
with this preparation is potential transmission to female partners or children
on close skin contact.
4. Testosterone buccal pellet. This plastic tablet is placed along the gum line
twice daily. Local discomfort (irritated gums) and the need for twice-daily
dosing sometimes limit use.
5. Subcutaneous testosterone pellet (Testopel) involves implantation of three
to six 75 mg testosterone pellets every 3 to 6 months, into the subdermal fat
of the buttocks, lower abdominal wall, or thigh with a trocar under sterile
conditions using a local anesthetic. This is not a very frequently used mode
 of testosterone replacement due to pellet extrusion, fibrosis, infection, and
the need for an incision to implant the Testopel.
6. Nasal testosterone gel (Natesto). Natesto is administered into each nostril
by a metered-dose pump applicator three times daily. The risk of
testosterone transfer from a patient to his partner or children is mitigated,
but the complications of testosterone replacement are acne, polycythemia,
prostate enlargement, possible growth-promoting effect on undiagnosed
prostate cancer, worsening of obstructive sleep apnea (OSA), peripheral
edema, and gynecomastia.
Oral alkylated androgens are not recommended due to adverse effects of
decreased high-density lipoprotein,37 increase in low-density lipoprotein (LDL),
and also incidence of cholestatic jaundice and peliosis hepatitis.
Monitoring Testosterone Replacement Therapy
Prostate-specific antigen (PSA), blood counts (for hematocrit), and lipid levels
should be checked 3 to 6 months after initiation of testosterone replacement and
at least yearly thereafter. Routine clinical evaluation for leg edema, worsening of
sleep apnea, and prostate enlargement is also recommended. Pharmacologic use
of testosterone may also reduce sperm count by reducing the intratesticular
testosterone concentration that is manyfold higher than serum concentrations. If
PSA elevation is noted after testosterone replacement, prostate evaluation with
possible biopsy is recommended. Prostatic carcinoma is a contraindication to
testosterone replacement.
THE OVARIES
Early Ovarian Development
If no Y chromosome or TDF is present, the gonad, by default, forms an ovary;
the cortex develops, the medulla regresses, and oogonia begin to develop within
follicles. The oogonia are derived from the primitive germ cells by a series of
about 30 mitoses, far fewer than the number required for spermatogenesis.
Beginning at about the end of the 3rd month, the oogonia enter meiosis I, but
this process is arrested at a stage called dictyotene, in which the cell remains
until ovulation occurs many years later (this cell is called primary oocyte). Many
of the oogonia degenerate before birth, and only about 400 mature into ova
during the 30 years or so of sexual maturity of the female. It is evident that the
gonads are paired bilateral structures; in very rare circumstances, the
developmental processes may be different on either side. Estrogen formation in
the fetal ovary begins in early development despite primordial follicles not
having begun forming until the second trimester of pregnancy (at 16 weeks of
gestation). The gonadotropins from the pituitary gradually take over the role of
maternal placental hCG, and fetal pituitary LH and FSH peak near midgestation
and then fall to low concentrations at birth. Postpartum, a smaller peak of LH
and FSH occur, which stimulates steroid secretion leading to neonatal milk
production from the breast.
Pubertal Changes of Ovarian Function
The onset of puberty is characterized by increasing secretion of LH and FSH that
stimulates gonadal activity and is driven by increased activity of the
hypothalamic GnRH neurons. In the ovary, both LH and FSH are involved in the
control of steroidogenesis, and there are numerous isoforms of circulating LH
and FSH and their biological potency depends on the degree of glycosylation,
which is associated with differences in assays for LH and FSH. The genes
coding LH and FSH receptors are on chromosome 2p21. Inactivating mutations
of the β-chain of the LH receptor have been described. Before the onset of
puberty, both LH and FSH are secreted in small amounts, but as puberty
approaches, the amplitude of LH and FSH pulsatile secretions increases and the
nocturnal rise in LH secretion increases. The nocturnal rise disappears with
adulthood.
The ovaries are paired organs that, like the male gonads, perform the dual
functions of gamete (ovum) and steroid hormone production.38, 39, 40 Unlike in
the male, the primordial reproductive cells in the female typically produce a
solitary gamete. Ovarian and menstrual events are carefully synchronized by a
complex interplay of hormones among the hypothalamus, pituitary, and ovaries
to prepare the uterus for implantation of an embryo. In the absence of
implantation, the uterine lining is shed, resulting in menses.41,42
The length of the menstrual cycle is the time between any two consecutive
cycles. The typical duration is 25 to 35 days, with average menstrual flow about
3 to 6 days.42
Functional Anatomy of the Ovaries
The ovaries are oval organs that lie in the pelvic fossa, formed by the posterior
and lateral pelvic wall, and attach to the posterior surface of the broad ligament
by the peritoneal fold, otherwise known as the mesovarium. They are positioned
near the fimbrial end of the fallopian tubes, which are connected to the uterine
cavity. An adult ovary averages 2 to 5 cm in length, weighs an average of 14 g,
and typically contains 2 to 4 million primordial follicles.43 These primordial
follicles are present at birth; however, maturation is blocked until puberty.
Following the onset of puberty, each ovarian cycle is marked by recruitment of a
few primordial follicles for maturation. Typically, all but one of these follicles
will then atrophy, in a process termed the follicular phase.
The single remaining follicle—known as the graafian follicle—is composed
of an outer and inner layer (the theca externa and theca interna, respectively)
encasing a central fluid-filled cavity and a layer of cells known as the granulosa
layer.44, 45, 46 The maturing ovum attaches to the inside of the follicle via cells
derived from granulosa cells, called cumulus cells. During the luteal phase of
the ovarian cycle, the graafian follicle releases its ovum in response to ovarian
stimulation by LH. When the ovum is extruded, the graafian follicle undergoes a
morphologic change with hypertrophy of the theca and granulosa cells to
become the corpus luteum. This process is called luteinization. The corpus
luteum is rich in cholesterol and acts as a substrate for continued production of
progesterone and estrogen, maintaining the endometrium for conception. If
conception or implantation fails to occur, the endometrium is shed and the
corpus luteum atrophies to an atretic follicle.
Hormonal Production by the Ovaries
As in the adrenal glands and the testes, the steroidogenic pathway and synthetic
enzymes are present in the ovaries. Cholesterol is either synthesized from acetate
or actively transported from the LDL particle in blood and then used as a
substrate for hormonal production.47
Estrogen
Naturally synthesized estrogens are carbon-18 compounds. The principal
estrogen produced in the ovary is estradiol. Estrone and estriol are primarily
metabolites of intraovarian and extraglandular conversion. Estrogens promote
breast, uterine, and vaginal development and also affect the skin, vascular
smooth muscles, bone cells, and the central nervous system.48 The lack of
estrogen that naturally occurs with the onset of menopause leads to atrophic
changes in these organs.49 During the reproductive period, it is estrogen that is
responsible for follicular phase changes in the uterus, with deficiency resulting
in irregular and incomplete development of the endometrium.
Progesterone
Progesterone is a carbon-21 compound within the steroid family and is produced
by the corpus luteum. Progesterone induces the secretory activity of those
endometrial glands that have been primed by estrogen, readying the
endometrium for embryo implantation. Other effects include thickening of the
cervical mucus, reduction of uterine contractions, and thermogenic effect, in
which basal body temperature rises after ovulation. This effect is of clinical use
in marking the occurrence of ovulation. Progesterone is the dominant hormone
responsible for the luteal phase, and deficiency results in failure of implantation
of the embryo.50
Androgens
Ovaries produce the androgens androstenedione, dehydroandrostenedione,
testosterone, and DHT, all of which are carbon-19 compounds. Excess
production of ovarian androgens in women leads to excess hair growth
(hirsutism), loss of female characteristics, and—in severe cases—development
of overt male secondary sexual features (masculinization or virilization).50, 51,
52 Unlike estrogen, which is not produced in the ovary after menopause, ovarian
androgen synthesis continues well into advanced age.53
Others
Inhibins A and B, which are produced by the ovaries, are hormones that inhibit
FSH production.54 Activin is a hormone that enhances FSH secretion and
induces steroidogenesis.54 Folliculostatin, relaxin,55 follicle regulatory protein,
oocyte maturation factor, and meiosis-inducing substance are hormones that
appear to have important, yet not clearly characterized, functions.
The Menstrual Cycle
By convention, the menstrual cycle is considered to start on the 1st day of
menses (day 1). The menstrual cycle consists of two phases of parallel events
occurring at the ovaries and endometrium. Within the ovaries, these events are
known as the follicular and luteal phases, while the concurrent endometrial
events are known as the proliferative and secretory phases.56
The Follicular Phase
The follicular phase begins with the onset of menses and ends on the day of LH
surge. Early in the follicular phase, the ovary secretes very little estrogen or
progesterone. A rise in FSH, however, stimulates estrogen production. The
estrogen secreted by the developing follicle within the ovary stimulates uterine
epithelial cells, blood vessel growth, and endometrial gland development to
increase the thickness of the endometrium.
The Luteal Phase
Estrogen levels peak 1 day before ovulation, at which point a positive feedback
system results in an LH surge. The start of the luteal phase is marked by the
extrusion of the ovum approximately 36 hours after this LH surge, with
subsequent luteinization of the graafian follicle to form the corpus luteum. The
corpus luteum secretes progesterone to aid in the implantation of the embryo.
The intense secretory capacity of the uterine glands aids the implantation of the
embryo. In the absence of fertilization, with a gradual decline in the production
of progesterone and estrogen by the corpus luteum, there is a loss of endometrial
blood supply; this results in shedding of the endometrium approximately 14 days
after ovulation occurred. The typical duration of menstrual bleeding is 3 to 5
days, with blood loss averaging 50 mL. Onset of menses marks the end of the
luteal phase.
Hormonal Control of Ovulation
The central control of FSH and LH secretion resides in the GnRH pulse
generator of the arcuate nuclei and medial preoptic nuclei of the hypothalamus.56
Positive and negative feedback responses exist among estrogen, progesterone,
LH, and FSH production. It is because of the lack of estrogen after menopause
that both FSH and LH levels rise.57 During reproductive years, FSH levels are
elevated early in the follicular phase. A midcycle surge in LH production
stimulates a series of events that culminate in ovulation, with FSH levels falling
after this event. Any injury to the hypothalamus or the presence of either
psychosocial or physical stressors leads to changes in these hormonal cues and
results in anovulation and amenorrhea.58
CASE STUDY 22.1
A 39-year-old woman presented with hot flashes and irregular menstrual
cycles for 6 months. Clinical examination did not reveal abnormality.
Laboratory evaluation reveals the following: CBC, normal; blood glucose,
89 mg/dL; TSH, 1.5 mIU/L; FSH, 128 IU/L; and LH, 30 IU/L.
This clinical situation is consistent with one of the following:
1. PCOS
2. Prolactinoma
3. Pituitary tumor
4. Menopause
5. Hypothalamic hormone deficiency
Pubertal Development in the Female
As with males, puberty in females consists of a sequence of hormonally
mediated events resulting in the development of secondary sexual characteristics
and attainment of final adult height. Thelarche (development of breast tissue) is
typically the earliest sign of sexual development, followed by development of
pubic hair. Menarche, or initiation of menses, occurs an average of 2 to 3 years
after the onset of puberty.
Precocious Sexual Development
Precocious sexual development occurs in response to premature exposure of
tissues to sex steroids from any source and is distinguished from precious
puberty, which can be arrested by suppression of GnRH with analogs of GnRH
that will suppress LH. If untreated, precious puberty or sexual development can
lead to short stature. Premature breast development is characterized by isolated
breast development and occurs in response to earlier estrogen secretion, albeit at
low circulating concentrations. Premature adrenarche may occur between 4 and
8 years of age and is characterized by pubic hair growth, and most commonly,
precious puberty does not ensue. Gonadotropins and gonadal steroid secretion
help differentiate between them. DHEA and dehydroepiandrosterone sulfate
(DHEAS) are elevated for age but match the child's bone age.
In girls with delayed puberty, sex steroids and gonadotropins are low, but
they continue growing and may be tall because growth hormone (GH) and other
pituitary hormones are unaffected unless pituitary or hypothalamic dysfunction
is present.
Devised by Marshall and Tanner as a way to determine pubertal staging, the
Tanner staging system, outlined in Table 22.2, is used to monitor and assess the
growth stages of breast and pubic hair.59
TABLE 22.2 Tanner Staging of Breast and Pubic Hair Development in
Females
Menstrual Cycle Abnormalities
The menstrual cycle ranges from 25 to 35 days, with an average of 28-day
duration. The average age of menopause in the United States is between 45 and
55 years, with the median at 53 years.57
Amenorrhea is defined as the absence of menses. Primary amenorrhea is
used to describe a woman who has never menstruated by age 16 years, while
secondary amenorrhea is used to describe a woman who has had at least one
menstrual cycle followed by absence of menses for a minimum of 3 to 6
months.58 Frequency of the different etiologies for amenorrhea, both primary
and secondary, is listed in Table 22.3.
TABLE 22.3 Etiologies of Amenorrhea
Oligomenorrhea refers to infrequent irregular menstrual bleeding, with cycle
lengths in excess of 35 to 40 days. Uterine bleeding in excess of 7 days is
dysfunctional and is termed menorrhagia. In a patient with infertility, the
diagnosis of inadequate luteal phase is made when the luteal phase is less than
10 days or when an endometrial biopsy indicates the progression of endometrial
changes is delayed or out of phase, resulting in implantation failure.60 The
multiple causes of male and female infertility are shown in Table 22.4.
TABLE 22.4 Causes of Infertility
 Hyperthecosis
Type 3. Hyperthalamic hypogonadism (elevated FSH and/or LSH)
Premature ovarian failure
Turner's syndrome

GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone;

LH, luteinizing hormone.

The principles underlying the evaluation of disorders of normal menstrual

functions, as outlined by the World Health Organization (WHO), are the same
for ovarian and pituitary dysfunction (Box 22.2). A diagnostic approach to
secondary amenorrhea is outlined in Figure 22.2.

BOX 22.2 Classification of Amenorrhea by

WHO Guidelines
Type 1. Hypothalamic hypogonadism (low or normal FSH and/or LH) FIGURE 22.2 Diagnostic approach to secondary amenorrhea. PRL, prolactin;
Hypothalamic amenorrhea (anorexia nervosa, idiopathic, exercise FSH, follicle-stimulating hormone; TSH, thyroid-stimulating hormone; hCG,
induced) human chorionic gonadotropin.
Kallmann's syndrome
Isolated gonadotropin deficiency Hypogonadotropic Hypogonadism
Type 2. Estrogenic chronic anovulation (normal FSH and LH)
Polycystic ovarian syndrome (LH > FSH in some patients 2:1 or Hypogonadotropic hypogonadism, or gonadotropin (FSH and LH) deficiency
greater) resulting in decreased sex steroid production, is a common cause of secondary
amenorrhea. There are many physiologic and pathologic causes of
hypogonadotropic hypogonadism, including weight loss as associated with
anorexia nervosa or various disease processes, intense physical exercise
(commonly termed runner's amenorrhea), and pituitary tumors that disrupt
secretion of FSH or LH.58 Prolactin production by prolactinomas can have
similar effects. Any secondary cause of chronic hypogonadism can induce
pathologic bone loss, resulting in osteopenia or, if severe, osteoporosis
(“athlete's triad”: constituted by amenorrhea, eating disorder, and osteoporosis).
CASE STUDY 22.2
isolation or in association with other endocrine gland failure such as
hypoparathyroidism, hypothyroidism, or hypoadrenalism.62
CASE STUDY 22.3
A 24-year-old man presented with a history of hay fever, which had been
treated with antihistamines. He relates diminished smell. He continues to
grow slowly, and pubertal development has been slow. The man denies
erections or nocturnal emissions.

A 49-year-old woman presented with increased hair growth for the past 6
months that started abruptly; she had male pattern hair loss, as well. On
MANAGEMENT
examination, she had temporal loss of hair and clitorimegaly. Laboratory Testosterone replacement therapy
evaluation revealed the following: testosterone, 360 ng/dL; FSH, 12 IU/L; Sexual maturity
LH, 9 IU/L; and a normal prolactin level. Later desired fertility
The next step in the evaluation is one of the following:
GnRH pulsatile therapy produced a normal sperm count in 4 months
1. DHEAS level and the man's wife became pregnant.
2. Repeat FSH and LH levels
3. Fasting blood sugar level questions
4. Fasting lipid level
5. Computed tomography of adrenal and ovaries
1. What is the level of the defect?
2. What is the significance of the body measurements?
3. What are the diagnostic considerations?
Hypergonadotropic Hypogonadism
4. What test(s) might be obtained to make the diagnosis?
Hypergonadotropic hypogonadism is characterized by ovarian failure resulting 5. What constitutes normal fertility?
in elevation of FSH concentrations, with or without LH elevations. Ovarian
failure occurs naturally between 45 and 55 years of age in American women. 6. How will you counsel this man when he asks if he can have children?
When the depletion of oocytes and follicles occurs at the expected time, it is
termed menopause. Menopause is a natural, inevitable event that results in
elevation of FSH and LH levels, with low levels of estrogen.57
Premature ovarian failure is defined as primary hypogonadism in a woman
before the age of 40 and can be a result of congenital chromosomal abnormality
(e.g., Turner's syndrome61) or premature menopause.62 Patients with Turner's
syndrome do not complain of the same hot flashes experienced by patients with
secondary hypergonadotropic hypogonadism. Premature menopause can occur in
 TABLE 22.5 Causes of Hirsutism

Polycystic Ovary Syndrome

This common disorder can present in many ways: infertility, hirsutism, chronic
anovulation, glucose intolerance, hyperlipidemia or dyslipidemia, and
hypertension.50, 51, 52 The onset is often perimenarcheal, chronic, and notable
for its slow progression. Investigations for this disorder involve estimation of
free testosterone, SHBG, FSH, LH, fasting glucose, insulin, lipid levels,
DHEAS, prolactin, and ± AMH levels. Ovarian ultrasound reveals multiple cysts
in many patients (about 30% of patients do not have ovarian cysts). Most
patients with this disorder are overweight; however, some patients with
polycystic ovary syndrome (PCOS), especially of eastern Asian or South
American descent, are of normal weight. Most symptoms and laboratory
abnormalities are reversed with weight loss and increased physical activity. The
drug Glucophage (metformin), commonly used for the treatment of diabetes, is
useful in this condition, even in the absence of diabetes. Although not U.S. Food
and Drug Administration approved for this use, it reportedly can normalize
menstrual cycles and improve conception rates.63
Hirsutism should only be considered in the context of a woman's ethnic
Hirsutism origin. Women of Italian, eastern European, south Asian, and Irish descent
Hirsutism is an abnormal, abundant, androgen-sensitive terminal hair growth in possess more androgen-sensitive terminal hair than do most northern European
areas in which terminal hair follicles are sparsely distributed or not normally women, making a careful elicitation of ethnic background important prior to
found in women (Box 22.3). Typical causes of hirsutism are listed in Table initiation of an extensive laboratory evaluation in a woman born in the United
22.5.51 States. It is estimated that about 5% to 10% of American women have hirsutism,
which can be quantified using a measurement technique known as the modified
Ferriman-Gallwey Scale that identifies nine areas (lip, chin, sideburn region,
BOX 22.3 Classification of Hirsutism51 neck, chest, abdomen, upper and lower back, and thigh) for assessment and
allots points on a scale of 1 to 4 based on hair thickness and pigmentation. A
Functional (normal androgen levels with excess hair growth) or true score of higher than 8 is consistent with a diagnosis of hirsutism.64 Hormonal
androgen excess (elevated androgens) abnormalities associated with hirsutism are summarized in Table 22.6.
Ovarian (LH mediated) or adrenal (adrenocorticotropin hormone
mediated)
TABLE 22.6 Androgen Levels in Hirsutism and Virilization
Peripheral conversion of androgens (obesity)
Tumoral hyperandrogenism (ovarian, adrenal)
Chorionic gonadotropin mediated
 growth spurt. Sleeve and pant lengths increased every 4 to 6 months.

questions
1. At what level is the defect in this case?
Modified from Demers LM. Hirsutism and Virilization, News and Views. Washington, DC: American
Association for Clinical Chemistry; 1989. 2. What diagnostic possibilities would explain the endocrine data?
3. What treatment(s) would be available to
Estrogen Replacement Therapy Treat his androgen deficiency?
Estrogen replacement remains a contentious issue. The Women's Health b. Allow him to father children if he wanted fertility?
Initiative study enrolled 16,608 postmenopausal women who were placed on 4. His appearance shows the defect occurred:
conventional hormone replacement combinations. The study showed an overall Prior to birth (during fetal life)
increased incidence of invasive breast cancer (hazard ratio, 1.26), stroke, venous b. After birth (postnatal)
clot formation, coronary heart disease (CHD) events, and no benefit in cognitive
decline, with combined estrogen plus progestin therapy (however, unopposed
estrogen therapy alone was not associated with increase in either breast cancer or
CHD, suggesting that these risks may be conferred by the progestin component).
With HRT, reductions in bone loss, colon polyp formation, and menopausal
symptoms (hot flashes and vaginal dryness) were noted. The recently published
ELITE trial (Early versus Late Intervention Trial with Estradiol) results showed
decreased progression of subclinical atherosclerosis (as seen by slower increase
in carotid intima–media thickening) in menopausal women who were started on
HRT within less than or equal to 6 years of menopause, lending further credence
to the “timing hypothesis,” that is, younger women may indeed benefit from
HRT in terms of decreased CHD risk.66, 67, 68, 69 In large meta-analyses of
randomized controlled trials, including the Women's Health Initiative, a
significantly lower risk of CHD (hazard ratio, 0.68; 95% CI, 0.48 to 0.96) and of
death from any cause (hazard ratio, 0.61; 95% CI, 0.39 to 0.95) was found with
hormone therapy than with placebo among women who were younger than 60
years of age, less than 10 years past menopause, or both when they underwent
randomization.70

CASE STUDY 22.4

A school physical examination of a 17-year-old boy showed less pubic and
axillary hair than those of peers, penis and scrotum that were smaller, breast
tissue since age 13, no erections or nocturnal emissions, and no adolescent
 d. Testis
e. Adrenal cortex
For additional student resources, please visit at 5. The parent substance in the biosynthesis of androgens and estrogens is
http://thepoint.lww.com a. Cholesterol
b. Cortisol
questions c. Catecholamines
d. Progesterone
1. If serum levels of estradiol do not increase after injection of hCG, the patient 6. The biologically most active, naturally occurring androgen is
has a. DHEA
a. Primary ovarian failure b. Androstenedione
b. Pituitary failure c. Epiandrosterone
c. Tertiary ovarian failure d. Testosterone
d. Secondary ovarian failure 7. For the past 3 weeks, serum estriol levels in a pregnant woman have been
2. If a patient had a luteal phase defect, which hormone would most likely be steadily increasing. This is consistent with
deficient? a. A normal pregnancy
a. Progesterone b. Hemolytic disease of the newborn
b. Estrogen c. Fetal death
c. hCG d. Congenital cytomegalovirus infection
d. FSH 8. Which of the following is secreted by the placenta and used for the early
detection of pregnancy?
e. Prolactin
a. hCG
3. Which of the following is the precursor for estradiol formation in the
placenta? b. FSH
a. Fetal adrenal DHEAS c. LH
b. Maternal testosterone d. Progesterone
9. Chronic fetal metabolic distress is demonstrated by
c. Maternal progesterone
d. Placental hCG a. Decreased urinary estriol excretion and decreased maternal serum
estriol
e. Fetal adrenal cholesterol
4. Which of the following target tissues is incapable of producing steroidal b. Decreased estrogen in maternal plasma and increased estriol in
hormones? amniotic fluid
a. Adrenal medulla c. Increased estradiol in maternal plasma, with a corresponding increase
of estriol in amniotic fluid
b. Placenta
d. Increased urinary estriol excretion and increased maternal serum estriol
c. Ovary 10. Androgen secretion by the testes is stimulated by
 a. LH
b. FSH
c. Testosterone
d. Gonadotropins
11. A deficiency in estrogen during the follicular phase will result in
a. A failure of embryo implantation
b. An increased length of the menstrual cycle
c. A lack of graafian follicle release from the ovary
d. An incomplete development of the endometrium
12. Which hormone is responsible for an increase in body temperature at the
time of ovulation?
a. Progesterone
b. Estrogen
c. LH
d. FSH
e. Estradiol
13. A midcycle LH surge will stimulate which series of events?
a. An increase in FSH
b. A decrease in FSH
c. Anovulation
d. Amenorrhea
e. A decrease in progesterone production

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