2. Hormonal Control of Testicular Function
• The hypothalamus, located in the brain, generates a hormone called
gonadotropin-releasing hormone (GnRH) in a pulsatile fashion.
• GnRH 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.
• 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 or synthesized
within the Leydig cells.
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3. Hormonal Control of Testicular Function
• 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 that induces testosterone synthesis.
• Testosterone is the principal androgen hormone in the blood.
• It is largely bound, with 2%–3% free.
• About 50% of testosterone is bound to albumin and about 45% is bound to sex
hormone–binding globulin (SHBG).
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4. Hormonal Control of Testicular Function
• Testosterone and inhibin are the two hormones secreted by the testes that
provide feed-back control to the hypothalamus and pituitary.
• 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 8 AM and correlates with most laboratory
normal ranges, and the lowest level is found at about 8 PM.
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5. Physiologic Actions of Testosterone
• Prenatal Development: Early in development, embryos have primordial
components of the genital tracts of both sexes.
• The primitive gonads become distinguishable at about the seventh week of
embryonic stage.
• Both chorionic gonadotropins and fetal LH stimulate production of testosterone
by the fetal Leydig cells.
• Exposure of testosterone to the Wolffian duct leads to differentiation of the
various components of the male genital tract.
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6. Physiologic Actions of Testosterone
• Sertoli cells produce müllerian regression factor, which aids in regression of the
female primordial genital tract.
• The scrotal skin is rich in 5-reductase, which converts testosterone to DHT.
• Fetal exposure to drugs that block this hormone leads to feminization of the male
fetus.
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7. Physiologic Actions of Testosterone
• 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.
• Possible mood changes and aggression are undesired effects that may occur
during puberty.
• The linear growth effects of testosterone are finite, with epiphysial 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.
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8. Physiologic Actions of Testosterone
• Effect on Spermatogenesis: Stimulation of Leydig cells induces production of
testosterone.
• Testosterone, acting with FSH, has paracrine effects on the seminiferous and
Sertoli cells inducing spermatogenesis.
• Exogenous overuse or abuse of testosterone, such as occurs with some athletes,
will reduce the high intra testicular concentration of testosterone, leading to
reduction of sperm production.
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9. Physiologic Actions of Testosterone
• Effect on Secondary Sexual Effects: Testosterone has growth promoting effects
on various target tissues.
• The secondary sex characteristics that develop during puberty are maintained
into late adulthood by testosterone.
• The prostate enlarges progressively during adulthood, while exposure of scalp
hair results in regression of the hair follicles.
• Loss of secondary sexual characteristics 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.
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10. Disorders of Sexual Development and Testicular Hypofunction
• Pubertal development could be premature (precocious) or delayed, even if
development is normal at birth.
• Hypergonadotropic Hypogonadism: Hypergonadotropic hypogonadism
incorporates a group of disorders characterized by low testosterone, elevated
FSH or LH, and impaired sperm production.
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11. Hypergonadotropic Hypogonadism
• Klinefelter’s Syndrome: Klinefelter’s syndrome occurs in about 1 of 400 men and
is caused by the presence of an extra chromosome.
• The most common karyotype is 47,XXY.
• Men with this disorder have small (2.5 cm), firm testicles.
• Gynecomastia (enlargement of the male breast) can also be present at the time
of diagnosis.
• Due to reduced production of testosterone, FSH and LH levels are elevated.
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12. Hypergonadotropic Hypogonadism
• Testicular Feminization Syndrome: Testicular feminization syndrome is the most
severe form of androgen resistance syndrome, resulting in lack of testosterone
action in the target tissue.
• As a result of the lack of testosterone effect, the physical development pursues
the female phenotype, with fully developed breast and female distribution of
fat and hair.
• Most men present for evaluation of primary amenorrhea, at which time the lack
of female internal genitalia becomes apparent.
• The testicles are often undescended, and failure to promptly remove these
organs results in malignant transformation.
• Biochemical evaluation reveals normal levels of testosterone with elevated FSH
and LH levels.
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13. Hypergonadotropic Hypogonadism
• 5-Reductase Deficiency: The genotype in 5-reductase deficiency is XY.
• A reduction in levels of the enzyme 5-reductase results in decreased
testosterone levels.
• Physical development is similar to the female phenotype until puberty when
residual enzyme activity sufficiently converts testosterone to
dihydrotestosterone, resulting in development of a male phenotype.
• Myotonic Dystrophy: Myotonic dystrophy is inherited in an autosomal dominant
fashion and presents with hypogonadism, muscle weakness, frontal balding,
diabetes, and muscle dystonia.
• Testicular failure typically presents in the fourth decade of life.
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14. Hypergonadotropic Hypogonadism
• Testicular Injury and Infection: Post pubertal mumps infection can result in
mumps orchitis and permanent testicular injury.
• Testicular damage due to viral orchitis and HIV infection has also been reported.
• Radiation and chemotherapy for cancer can also result in long-term damage.
• Sertoli Cell–Only Syndrome: Sertoli cell–only syndrome is characterized by a lack
of germ cells.
• Men present with small testes, high FSH levels, azoospermia, and normal
testosterone levels.
• Testicular biopsy is the only procedure to confirm this diagnosis.
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15. 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: 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.
• The associated defects, such as anosmia (inability to smell) and midline defects
(cleft palate and lip), should alert the clinician to suspect this disorder.
• Certain men also have red-green color blindness, congenital deafness, or
cerebellar dysfunction.
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16. Hypogonadotropic Hypogonadism
• Hyperprolactinemia: Prolactin elevation resulting from any cause (drug induced
or prolactin-producing tumors of the pituitary) can result in hypogonadotropic
hypogonadism.
• Age: There is a gradual reduction in testosterone after age 30, with an average
decline of about 110 ng/dL every decade.
• Age is also associated with elevation of SHBG by about 1% per year.
• Total testosterone levels may be normal in aging men but the free (unbound)
levels of testosterone are more reliable indicators of biochemical reduction.
• The associated features of reduced secondary sex hair growth, loss of muscle
bulk and strength, and loss of bone density are corroborative evidence
indicative of the lack of tissue effects of testosterone.
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17. Diagnosis of Hypogonadism
• Both clinical and biochemical features must be met to make the diagnosis of
hypogonadism.
• Testosterone levels have a circadian rhythm and the time of sampling must be
considered.
• Multiple estimation of free and bound testosterone levels should be done on different
days before a diagnosis of hypogonadism is made.
• The distinction between primary (disease or destruction of the testes) versus secondary
(disease or destruction of the pituitary) is relatively easy to make.
• FSH and/or LH levels are elevated in primary hypogonadism and are inappropriately
normal or low with secondary etiologies.
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18. Diagnosis of Hypogonadism
• 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.
• Clinical signs and symptoms of hypogonadism (e.g., loss of secondary sexual
characteristics, osteoporosis) should be corroborated with low testosterone
levels.
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20. Estrogen
• The ovaries are paired organs that, like the male gonads, perform the dual
functions of gamete (ovum) and steroid hormone production.
• 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 extra glandular
conversion.
• Estrogens promote breast, uterine, and vaginal development and affect the
skin, vascular smooth muscles, bone cells, and the central nervous system.
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21. Progesterone
• Progesterone is a carbon-21 compound within the steroid family and is produced
by the corpus luteum.
• Progesterone induces thickening of the cervical mucus, reduction of uterine
contractions, and the 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.
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22. Androgens
• Ovaries produce the androgens androstenedione, dehydroandrostenedione,
testosterone, and dihydrotestosterone, 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).
• Unlike estrogen, which is not produced in the ovary after menopause, ovarian
androgen synthesis continues well into advanced age.
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23. Others
• Inhibin A and B, which are produced by the ovaries, are hormones that inhibit
FSH production.
• Activin is a hormone that enhances FSH secretion and induces steroidogenesis.
• Folliculostatin, relaxin, follicle regulatory protein, oocyte maturation factor, and
meiosis-inducing substance are hormones that appear to have important, yet
not clearly characterized, functions.
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24. Hormonal Control of Ovulation
• The central control of FSH and LH secretion resides in the GnRH pulse generator
of the hypothalamus.
• 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.
• During reproductive years, FSH levels are elevated early in the follicular phase.
• A midcycle surge in LH production stimulates a series of events that culminates
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.
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25. 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 2–3 years after the
onset of puberty.
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26. Menstrual Cycle Abnormalities
• The menstrual cycles ranges from 25 to 35 days, with an average 28-day
duration.
• The average age of menopause in the United States is between 45 and 55 years
of age with the median at age 53.
• Amenorrhea is defined as the absence of menses.
• Primary amenorrhea describes when a woman has never menstruated, while
secondary amenorrhea is used to describe a woman who has had at least one
menstrual cycle followed by absences of menses for a minimum of 3–6 months.
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28. Menstrual Cycle Abnormalities
• Oligomenorrhea refers to infrequent of irregular menstrual bleeding, with cycle
lengths in excess of 35–40 days.
• Uterine bleeding in excess of 7 days is dysfunctional and is termed menorrhagia.
• The multiple causes of male and female infertility are shown in Table 21-4.
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30. Hypogonadotropic Hypogonadism
• Hypogonadotropic hypogonadism, or gonadotropin (FSH and LH) deficiency
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.
• Prolactin production by prolactinomas can have similar effects.
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31. Hypergonadotropic Hypogonadism
• Hypergonadotropic hypogonadism is characterized by ovarian failure resulting
in elevation of FSH concentrations, with or without LH elevations.
• Ovarian failure occurs naturally between 45 and 55 years of age in American
women.
• 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.
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32. Hypergonadotropic Hypogonadism
• 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 syndrome) or premature menopause.
• 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 isolation or in association with other
endocrine gland failure such as hypoparathyroidism, hypothyroidism, or
hypoadrenalism.
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33. Polycystic Ovary Syndrome (PCOS)
• This common disorder can present in many ways: infertility, hirsutism, chronic
anovulation, glucose intolerance, hyperlipidemia or dyslipidemia, and
hypertension.
• The onset is often perimenarchial, chronic, and notable for its slow progression.
• Investigations for this disorder involve estimation of free testosterone, SHBG,
FSH, LH, fasting glucose, insulin, and lipid levels.
• Ovarian ultrasound reveals multiple cysts in many patients (about 30% of
patients do not have ovarian cysts).
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34. Hirsutism
• Hirsutism is abnormal, abundant,
androgen-sensitive terminal hair growth
in areas in which terminal hair follicles
are sparsely distributed or not normally
found in women.
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36. Hirsutism
• Hirsutism should only be considered in the context of a woman’s ethnic origin
• Women of Italian, eastern European, eastern Indian, and Irish descent possess
more androgen-sensitive terminal hair than do most northern European
women, making a careful elicitation of ethnic background important prior to
initiation of an extensive laboratory evaluation in a woman born in the United
States
• It is estimated that about 5%–10% of American women have hirsutism, which can
be quantified using a measurement technique known as the Ferriman-Gallwey
Scale that identifies nine areas (lip, chin, sideburn region, neck, chest, abdomen,
upper and lower back, and thigh) for assessment and allots points on a scale of
1–4 based on hair thickness and pigmentation.
• A score of higher than 8 is consistent with a diagnosis of hirsutism.
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