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Endocrinology, the branch of medicine that deals with the chemical
communication between cells and organs via hormone messengers (as distinct
from neurogenic and immune communications), is concerned largerly with the
hormones themselves and the principal organ systems that synthesize the
hormones namely the pituitary, the thyroid, the parathyroid, the adrenal glands,
the gonads and the pancreas.1,2 Endocrine disorders constitute a major health
problem in the societies. As the etymology of the term hypogonadism suggests,
this condition centers on underfunctioning gonadseither testes or ovaries.
Hypogonadism is defined as inadequate gonadal function, as manifested by
deficiencies in gametogenesis and/or the secretion of gonadal hormones. Female
hypogonadism refers to deficient or abnormal function of the hypothalamic
pituitaryovarian axis that clinically presents with menstrual cycle disturbances.
Female hypogonadism can be due to a congenital or acquired cause, and the
defect can be at the level of the hypothalamus, pituitary or ovary. Hypogonadism
can develop before and after puberty. It has different sign and symptoms. 3,4,5

Hypogonadotropichypogonadism is defined as a deficiency of the pituitary

secretion of follicle-stimulating hormone and luteinizing hormone, which results
in the impairment of pubertal maturation and of reproductive function. In the
absence of pituitary or hypothalamic anatomical lesions and of anosmia
(Kallmann syndrome), hypogonadotropichypogonadism is referred to as isolated
hypogonadotropichypogonadism (IHH).1 Hypergonadotropichypogonadism in
males reflects primary testicular dysfunction and is characterized by elevated
serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and low
serum testosterone levels.6
2.1. Definition

Hypogonadism is defined as inadequate gonadal function, as manifested by

deficiencies in gametogenesis and/or the secretion of gonadal hormones. 7 The
major type of hypogonadism which will be discuss in this paper are
hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. These
disorders can occur on both male and female.
2.2 Epidemiology
Hypogonadism affects 2 to 4 million men in the United States and becomes
increasingly prevalent with age. A study reported that approximately 12%, 20%,
30%, and 50% of men in their 50s, 60s, 70s, and 80s, are hypogonadal. Other
factors, such as rising prevalence of obesity and type 2 diabetes mellitus are
expected to further raise the incidence of male hypogonadism. For women, the
incidence of hypogonadism in females is equal to that in males. No increase in
mortality exists in patients with hypogonadism. Morbidity for men and women
includes infertility, anemia and an increased risk of osteoporosis.9,10
2.3. Etiology
Male hypogonadism can be classified in four forms: (1) primary forms caused by
testicular insufficiency (congenital such as klinefelter syndrome, cryptorchidism,
etc., acquired form such as orchitis, testicular malignancy, etc.) (2) secondary
forms caused by hypothalamic-pituitary dysfunction (congenital such as,
kallmann syndrome, acquired such as pituitary tumor, drugs, systemic disease,
etc.) (3) late onset hypogonadism (aging), (4) male hypogonadism due to
androgen receptor insensitivity.
Female hypogonadism defined as hyposecretion of ovarian hormones. Its
etiopathogenesis is rather variable. The cause of ovarian hormone deficiency may
be within the ovaries themselves (primary female hypogonadism), in the
adenohypophysis (secondary female hypogonadism), or in the hypothalamus
(tertiary female hypogonadism).12

2.4. Pathophysiology
The gonad (ovary or testis) functions as part of the hypothalamic-pituitarygonadal axis. A hypothalamic pulse generator resides in the arcuate nucleus,
which releases luteinizing hormone (LH)-releasing hormone (LHRH), which is

also termed gonadotropin-releasing hormone (GnRH), into the hypothalamicpituitary portal system. Data suggest that a gene named KISS is important in the
development of the LHRH-secreting cells.15,16,17 In response to these pulses of
LHRH, the anterior pituitary secretes follicle-stimulating hormone (FSH) and LH,
which, in turn, stimulate gonadal activity. The increase in gonadal hormones
results in lowered FSH and LH secretion at the pituitary level, completing the
feedback loop. In the testes, LH stimulates Leydig cells to secrete testosterone,
whereas FSH is necessary for tubular growth. In the ovaries, LH acts on theca and
interstitial cells to produce progestins and androgens, and FSH acts on granulosa
cells to stimulate aromatization of these precursor steroids to estrogen.15,16

When ovaries are absent from birth or when they become nonfunctional before
puberty, female eunuchism occurs. In this condition, the usual secondary sexual
characteristics do not appear, and the sexual organs remain infantile. 2 When the
ovaries of a fully developed woman are removed, the sexual organs regress to
some extent so that the uterus becomes almost infantile in size, the vagina
becomes smaller, and the vaginal epithelium becomes thin and easily damaged.
The breasts atrophy and become pendulous, and the pubic hair becomes thinner.
The same changes occur in women after menopause.15,16,17
When the testes of a male fetus are nonfunctional during fetal life, none of the
male sexual characteristics develop in the fetus. Instead, female organs are
formed. When a boy loses his testes before puberty, a state of eunuchism ensues in
which he continues to have infantile sex organs and other infantile sexual
characteristics throughout life. When a man is castrated after puberty, some of his
male secondary sexual characteristics revert to those of a child and others remain
of adult masculine character. 15,16,17

Hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is








hypogonadism) results if the gonad does not produce the amount of sex steroid
sufficient to suppress secretion of LH and FSH at normal levels.

Hypogonadotropic hypogonadism may result from failure of the hypothalamic

LHRH pulse generator or from inability of the pituitary to respond with secretion
of LH and FSH. Hypogonadotropic hypogonadism is most commonly observed as
one aspect of multiple pituitary hormone deficiencies resulting from
malformations (eg, septooptic dysplasia, other midline defects) or lesions of the
pituitary that are acquired postnatally.15,16
2.5. Diagnosis
2.5.1. Male Hypogonadism
The diagnosis of hypogonadism in men is based on a combination of clinical signs
and symptoms and laboratory tests. Biochemical assessments for suspected
hypogonadism include measures of total testosterone, free testosterone, SHBG,
follicle-stimulating hormone, and luteinizing hormone. An inexpensive and
reliable screening test for hypogonadism is a morning serum total testosterone
level, which measures free testosterone plus protein-bound testosterone. A
morning sample is recommended, because testosterone levels demonstrate a
diurnal pattern in which the highest level is reached in the early morning hours.
Morning testosterone values <300 ng/dL (10.4 nmol/L) suggest hypogonadism
and should be confirmed by a second assay.14,15,16

If a repeat assay confirms low testosterone, luteinizing hormone (LH) should be

measured to determine whether the cause is primary or secondary. LH levels <2
ng/mL suggest a hypothalamic lesion (pituitary adenoma, trauma, etc), whereas
LH levels >10 ng/mL indicate primary testicular failure. Levels within the normal
range suggest an age-related, decreased hypothalamic response to declining
testosterone levels. In addition, serum prolactin should also be measured to rule
out the presence of a pituitary tumor.15,17
a. ADAM Questionnaire
In addition to laboratory tests and a careful physical examination, a brief
screening instrument has also been developed to aid in the diagnosis of
hypogonadism. Researchers at St. Louis University created the Androgen
Deficiency in the Aging Male (ADAM) questionnaire, which has been shown to

be a highly sensitive (88%) instrument but with low specificity (66%), largely due
to questions that identify patients with depression.
Table 1. ADAM quistionnare17


Indications for MRI

Magnetic resonance imaging (MRI) to detect a pituitary macroadenoma is
appropriate in men with low testosterone when the luteinizing hormone level is
also low or the prolactin level is elevated, especially in men younger than 50 years
who have no comorbidities consistent with secondary hypogonadism. Older men
with secondary hypogonadism should undergo MRI under the following
circumstances: (1) if the serum testosterone is very low (< 150 ng/dL) and if either
luteinizing hormone is normal or low or prolactin is increased, (2) if symptoms
such as visual changes or headache are present.
2.5.5. Female Hypogonadism
In female hypogonadism, the test that should be done include Estrogen level
(women) FSH level and LH level. Other tests may include blood tests
for anemia and iron, genetic tests, prolactin level (milk hormone), thyroid level.
Sometimes imaging tests are needed, such as a sonogram of the ovaries. If
pituitary disease is suspected, an MRI or CT scan of the brain may be done.16,17
2.6 Differential Diagnosis
Some of disorders that mimics to hypogonadism are 3-Beta-Hydroxysteroid
Dehydrogenase Deficiency, 5-Alpha-Reductase Deficiency, Adrenal Hypoplasia,
Adrenal Insufficiency, Ambiguous Genitalia and Intersexuality, Amenorrhea,

Androgen Insensitivity Syndrome, Congenital Adrenal Hyperplasia, Denys-Drash

Syndrome, Eating Disorder: Anorexia, Growth Failure, Hypopituitarism,
Hypothyroidism, Klinefelter Syndrome, Malnutrition, Menstruation Disorders,
Turner Syndrome

2.7 Treatment
In adult men, treatment for male hypogonadism depends on the cause and whether
concerned about fertility. Treatment can consists of (1) Hormone replacement for
hypogonadism caused by testicular failure, can use testosterone replacement
therapy, or TRT. TRT can restore sexual function and muscle strength and prevent
bone loss. If a pituitary problem is the cause, pituitary hormones may stimulate
sperm production and restore fertility. (2) Assisted reproduction, although there's
often no effective treatment to restore fertility in a man with primary
hypogonadism, assisted reproductive technology may be helpful. This technology
covers a variety of techniques designed to help couples who have been
unsuccessful in achieving conception. 18,19,20,21
In boys, testosterone replacement therapy (TRT) can stimulate puberty and the
development of secondary sex characteristics, such as increased muscle mass,
beard and pubic hair growth, and growth of the penis. Pituitary hormones may be
used to stimulate testicle growth. An initial low dose of testosterone with gradual
increases may help to avoid adverse effects and more closely mimic the slow
increase in testosterone that occurs during puberty. Several testosterone delivery
methods exist. Methods include: (a) testosterone injections are safe and effective.
Injections are given in a muscle about every two weeks. Several other testosterone
theraphy those can be applied are (b) patch each night to back, abdomen, and
upper arm or thigh; (c) gel that rub into the skin as the gel dries, the body absorb
testosteron through the skin; (d) gum and cheek (buccal cavity) which is the
striant, a small putty-like substance, delivers testosterone through the natural
depression above top teeth where your gum meets your upper lip (buccal cavity),
(e) by oral but isn't recommended for long-term hormone replacement, because it
may cause liver problems, raise cholesterol and increase risk of heart disease.23,24

In women, estrogen should be increased. To initiate pubertal development in girls,

HRT can be given orally as conjugated estrogen or as a patch applied twice
weekly. Transdermal application allows a very low starting dose of estrogen
which is desired in young girls with bone ages below 12 years. Starting at higher
doses may cause rapid closure of epiphyses and growth will be halted. Women
taking estrogen also need to take progesterone replacement unless they have
undergone a surgical removal of the uterus. Progesterone agents are added during
the last 12 to 14 days of the menstrual cycle to transform the proliferative inner
lining of the uterus (endometrium) into the secretory state.18,19,20,21,22









hypogonadotropichypogonadism, synthetic GnRH can be given in a pulsatile

fashion subcutaneously through a pump every 2 hours. GnRH therapy is
monitored by measuring LH, FSH, and testosterone levels every 2 weeks until
levels are in the normal range, at which point monitoring can be adjusted to every
2 months. GnRH can be used to initiate pubertal development, maintain
virilization and sexual function, and initiate and maintain spermatogenesis.25,26,27
Testosterone replacement, pulsatile GnRH therapy, and gonadotropin therapy are
contraindicated in men with prostate cancer, male breast cancer, or untreated
prolactinoma. Hypogonadism patient also need psycological counseling since it is
associated with mood disturbances, including depression, aggression, poor selfesteem, and learning problems. The goal of theraphy are to restore sexual
function, optimize bone density and osteoporosis; possibly normalize normalize
growth hormone level in elderly men; and restore fertility.21,22,25,28,29
2.7. Prognosis
Most cases of hypogonadism are treatable and the outlook is good.30,31 Many men
with permanent causes of hypogonadism (e.g., genetic causes, testicular damage,
pituitary injury) require lifelong therapy. Men with hypogonadism related to
critical illness or medicine use recover after resolution of the illness or
discontinuation of the medication that causes low testosterone (e.g., opiates,
glucocorticoids).32 Marked weight loss in men with obesity (e.g., with bariatric
surgery) may lead to recovery of gonadal state.The prognosis for patients with
tumors or other serious conditions depends on how well the underlying problem

can be treated. The prognosis for successful stimulation of spermatogenesis in

men with hypogonadotropichypogonadism treated with hCG/hMG is good and
not adversely affected by prior androgen treatment.32

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