Male Hypogonadism - Rivin

Primary Male Hypogonadism
& Testosterone Therapy
W. P. Rivindu H. Wickramanayake
Group no. 04a
4th Year 2nd Semester – 2018 September
Tbilisi State Medical University, Georgia

Male Reproductive System
 Development starts between the 7th and 12th week of gestation.
 The undifferentiated gonads develop into a fetal testis through expression of
the sex-determining region Y gene (SRY), a gene complex located on the
short arm of the Y chromosome.
 The fetal testis produces two hormones ;
a. Testosterone
i. For the development of the Wolffian ducts
ii. Formation of the Epididymis, Vas deferens and Seminal vesicle.
b. Anti-Müllerian hormone (AMH).
i. Regression of the Müllerian ducts.
 Testosterone is needed for development of the prostate, penis and scrotum.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282686/

 However, in these organs testosterone is converted into the more potent
metabolite dihydrotestosterone (DHT) by the enzyme 5a-reductase.
 The enzyme is absent in the testes, which explains why 5a-reductase
inhibitors do not have a marked effect on spermatogenesis.
 Intratesticular testosterone influence ;
a. Number of gonocytes per tubule increases 3x during the fetal period.
b. Maintain the spermatogenic process and to inhibit germ cell apoptosis.
 The seminiferous tubules of the testes are exposed to concentrations of
testosterone 25-100 times greater than circulating levels.
 Suppression of gonadotrophins (e.g. through excessive testosterone
abuse) results in a reduced number of spermatozoa in the ejaculate and
hypospermatogenesis.
 Complete inhibition of intratesticular testosterone results in full cessation of
meiosis up to the level of spermatids.

Hypogonadism
 “inadequate gonadal function, as manifested by
deficiencies in gametogenesis and/or the secretion
of gonadal hormones.”
 These abnormalities usually result from disease of
the testes (primary hypogonadism) or disease of
the pituitary or hypothalamus (secondary
hypogonadism).
 In occasional cases, a defect in the ability to
respond to testosterone is the cause of
hypogonadism.

 Hypergonadotropic Hypogonadism
(Primary)
 Increased FSH level
 Increased LH level
 Low testosterone level
 Impaired production of sperm
 Hypogonadotropic Hypogonadism
(Secondary)
 Low or low-normal FSH level
 Low or low-normal LH level
 Low testosterone level
 Impaired production of sperm

 Primary hypogonadism is more likely to be associated with a decrease in sperm
production than in testosterone production.
 Although many testicular diseases damage both the seminiferous tubules and the
Leydig cells, they usually damage the seminiferous tubules to a greater
degree.
 As a consequence, the sperm count may be low, and the serum FSH concentration
normal or high, yet the serum testosterone concentration remains normal.
 In contrast, in secondary hypogonadism, there is a proportionate reduction in
testosterone and sperm production.
 Primary hypogonadism is more likely to be associated with gynecomastia,
presumably due to the stimulatory effect of the supranormal serum FSH and LH
concentrations on testicular aromatase activity.
 This results in increased conversion of testosterone to estradiol .
Primary Hypogonadism vs Secondary Hypogonadism

General Manifestations
Before Puberty ;
 Small testes, phallus, and prostate
 Scant pubic and axillary hair
 Disproportionately long arms and
legs (from delayed epiphyseal
closure)
 Reduced male musculature
 Gynecomastia
 Persistently high-pitched voice
After Puberty ;
 Reduced sexual desire and activity,
 Decreased spontaneous erections,
 Loss of body hair and reduced
frequency of shaving,
 Infertility,
 Reduced muscle bulk and strength,
 Hot flushes and sweats,
 Height loss due to atraumatic fracture,
 Small or shrinking testes,
 Breast enlargement or tenderness

Less-specific symptoms ;
 Decreased energy, motivation, & initiative; sad or blue feelings, depressed
mood, dysthymia; poor concentration and memory; sleep disturbance &
increased sleepiness; increased body fat & diminished physical / work capacity.

Physical Examination
 The amount and distribution of body hair, including beard growth,
axillary hair, and pubic hair, should be noted, as should the presence of a
male pattern escutcheon.
 The presence and degree of gynecomastia. The presence of galactorrhea
would suggest pronounced hyperprolactinemia, usually associated with
some degree of hyperestrogenism.
 The testes should be measured (length and width) by using a Prader
orchidometer or calipers.
 Testicular consistency should be noted.
 If the germinal epithelium was damaged before puberty, the testes are
generally small and firm.
 If postpubertal damage occurred, the testes are usually small and soft.

 Some testicular disorders may selectively affect production of sperm without
influencing production of testosterone. These disorders may sometimes be
detected by careful physical examination, including determination of testicular
size and consistency.
 Because approximately 85% of testicular mass consists of germinal tissue, a
reduced germinal cell mass would be associated with a reduced testicular size
and a soft consistency.

 On examination of the scrotum, the presence of any masses or
varicoceles should be noted for further evaluation. For assessment of any
potentially significant varicocele, the patient should be asked to perform
a Valsalva maneuver, and the scrotal contents should be examined.
 The stretched penis should be measured (length and width) .
 With prepubertal onset of hypogonadism, the stature may assume
eunuchoid proportions, with a crown-to-pubis divided by a pubis-to-
floor ratio of <0.92 and an arm span more than 3 cm greater than the
height.
 A nonpalpable prostate suggests low testosterone levels. A prostate that
is normal for age suggests reasonably normal testosterone levels. Of
note, an enlarged prostate may not substantially diminish if once-normal
testosterone levels have decreased.

Differential Diagnosis
 Common ;
1. Klinefelter’s Syndrome
2. Uncorrected Cryptochordism
 Rare ;
1. Coonan's Syndrome
2. Mytonic Dystrophy
3. Mutations in the LH receptor or subunits
4. Type 1 Autoimmune Polyglandular Syndrome
 Less Common ;
1. Radiation
2. Chemotherapy
3. Orchitis
4. Trauma
5. Anorchia due to Bilateral Torsion or Vanishing Testes Syndrome
6. Medications (Ketoconazole)

Klinefelter's Syndrome
 Most common congenital abnormality, approx. 1 in 1000 live male
births.
 The clinical manifestation of a male with an extra X chromosome.
 The most common genotype is 47,XXY ,but greater and lesser
numbers of X chromosomes have also been reported, resulting in
karyotypes such as 48,XXXY and 46,XY/46,XXY mosaicism .
 46,XX males ; the development of testes in this setting is presumably
due to translocation of a small portion of chromosomal material
containing the testis-determining factor to an X chromosome.
 The 47,XXY genotype results from nondisjunction of the sex
chromosomes of either parent during meiotic division.
 While mosaicism probably results from nondisjunction during mitotic
division after conception.

 The greater the number of extra X chromosomes, the greater the
phenotypic consequences, both gonadal and extra-gonadal.
 Damage to the seminiferous tubules & usually damage to the Leydig cells
as well.
 The gonadal manifestations include almost invariably small, firm testes,
severely subnormal sperm count, infertility, elevated (FSH) and (LH)
concentrations, variably subnormal serum testosterone concentration and
decreased virilization .
 The damage may be increased if the patient also has cryptorchidism, the
incidence of which is increased in Klinefelter's .
 A psychosocial abnormality, unrelated to the hypogonadism, which causes
difficulty in social interactions throughout life & has been characterized
by "marked lack of insight, poor judgment and impaired ability to learn
from adverse experience" .

 Predisposition to develop morbidities later in life that are unrelated to
testosterone deficiency .
 These include:
 Pulmonary diseases such as chronic bronchitis, bronchiectasis, and emphysema
 Cancers, including germ cell tumors (particularly extragonadal tumors
involving the mediastinum) ,breast cancer & possibly non-Hodgkin lymphoma
 Varicose veins, leading to leg ulcers
 Systemic lupus erythematosus, probably due to the extra X chromosome
 Diabetes mellitus
 Mortality from breast cancer has been reported to be much higher in
Klinefelter syndrome than in the general population but that from
prostate cancer lower.

 Diagnosis of Klinefelter's syndrome
usually can be made by determining the
karyotype of the peripheral leukocytes.
 Testosterone deficiency and the
resulting hypogonadism, if present, can
be treated with testosterone .
 Hormone replacement is unlikely to
improve the other abnormalities.
Fertility has been achieved with assisted
reproductive technologies , but there are
important genetic implications of these
procedures .

Other Chromosomal Abnormalities
 The 46,XY/XO karyotype leads to a syndrome characterized by short stature
& features typical of Turner syndrome.
 The gonads vary from streak to dysgenetic to normal testes; as a result, the
sexual phenotype varies from complete female to complete male.
 If the patient has both a streak gonad and a dysgenetic testis ("mixed gonadal
dysgenesis"), the risk of gonadoblastoma is about 20 percent.
 Gonadectomy should therefore be performed in these patients.
 The 47,XYY karyotype was initially thought to be associated with
hypogonadism, but subsequent reports have not confirmed this relation.
 Microdeletions in specific regions of the long arm of the Y chromosome
are occur in up to 20 percent of men with azoospermia / severe oligospermia.
 Some of these men have no other testicular lesions, but cryptorchidism .

Mutation in the FSH and LH Receptor Genes
 Another rare cause of primary hypogonadism is a mutation in the FSH
receptor gene.
 One report described five men found to be homozygous for an
inactivating mutation of the FSH receptor. These subjects had variably
low sperm counts and inhibin B concentrations and high serum FSH
concentrations.
 LH receptor mutations result in
Leydig cell hypoplasia and
testosterone deficiency in the
first trimester in utero, resulting
in varying degrees of male
pseudohermaphroditism.

Cryptorchidism
 Testes that are undescended. It can be either Unilateral or bilateral.
 3 to 4% at birth, most testes ultimately descend.1-year incidence is about 0.8%.
 Normal testicular descent requires normal pituitary function &
dihydrotestosterone levels, the incidence is increased in Kallmann’s syndrome.
 The objective is to bring the undescended testicle into the scrotum before 1 to 2
years of age to improve fertility potential.
 A slight risk of a malignant lesion is associated with undescended testicles,
surgical placement into scrotum offers the opportunity for thorough examination.
 Clinical consequences depend upon whether one or both testes are cryptorchid:
 If only one testis is undescended, the sperm count will be subnormal in 25 to 33
percent & the serum FSH concentration will be slightly elevated. The presence
of these abnormalities suggests that both testes are abnormal, perhaps
congenitally, even though only one fails to descend.
 If both testes are undescended, the sperm count will usually be severely
subnormal and the serum testosterone may also be reduced.

Disorders of Androgen Biosynthesis
 A congenital decrease in testosterone synthesis and secretion can
result from mutations of the genes that encode the enzymes
necessary for testosterone biosynthesis.
 These mutations, all rare, involve the cholesterol side chain
cleavage enzyme, 3 beta-hydroxysteroid dehydrogenase, and 17
alpha-hydroxylase, both of which are present in the adrenal
glands as well as the testes, and 17 beta-hydroxysteroid
dehydrogenase, which is present only in the testes.
 Each of these mutations results in decreased testosterone secretion,
beginning in the first trimester of pregnancy, and therefore in
incomplete virilization.

Myotonic Dystrophy
 Classically, myotonic dystrophy is an autosomal dominant
disorder, characterized by hypogonadism, muscle weakness, and
frontal balding, that occurs only in male patients.
 Testicular failure usually occurs after age 40 years; thus, patients
often have children at risk for the disease. Testosterone levels may
be variably decreased in the setting of azoospermia and high
gonadotropin levels.
 Small testes and decreased sperm production are more common
than decreased serum testosterone levels.

Vanishing Testes Syndrome
(Congenital Anorchism / Prepubertal Functional Castrate)
 The initial manifestation is sexual immaturity in a male patient. Unclear cause,
but may be due to testicular torsion during fetal life after sufficient testosterone
exposure to produce masculinization of the reproductive tract.
 Impalpable testes - possibility of cryptorchidism. Increased FSH and LH
levels, low testosterone levels. If the LH levels are only minimally increased,
hCG stimulation testing of the gonad should be done. With vanishing testes
syndrome, no response would be demonstrated.
 A response to hCG stimulation would raise the possibility of intra-abdominal
testes, which would necessitate further evaluation because of the potential for
malignant transformation.
 In this setting, MRI is recommended to assess the possibility of a retained
intraabdominal dysgenetic gonad because this would be associated with an
increased risk of a malignant lesion and would necessitate removal.

Varicocele
 Varicosity of venous plexus within the scrotum is called a varicocele.
 Has long been considered a possible cause of damage to the
seminiferous tubules and thereby of infertility.

Infections - Mumps Orchitis
 Mumps orchitis is the infection most closely associated with
testicular damage.
 Orchitis is a much more common manifestation when mumps occurs
in adulthood than in childhood.
 The median age of men who got mumps orchitis in one study was 29.
 Testicular involvement of mumps causes painful swelling of the
testes, followed by atrophy.
 The seminiferous tubules are almost always severely affected, often
resulting in infertility, especially when both testes are involved;
 The Leydig cells also may be damaged, resulting in decreased
testosterone production.

Radiation
 Direct radiation to the testes, as in treatment for leukemia, will damage testes.
 Even indirect radiation to testes when they are shielded(as with radiation to the
inguinal lymph nodes for lymphoma) will damage the seminiferous tubules.
 The degree of damage is proportionate to the amount of radiation exposure.
 Radioactive iodide has been reported to cause a decrease in the sperm count
when doses of several hundred mCi are administered to treat thyroid cancer.
Alkylating and Antineoplastic Agents
 Alkylating agents, such as cyclophosphamide, chlorambucil, cisplatin, and
busulfan can damage the seminiferous tubules to a degree sufficient to cause
azoospermia and markedly elevated serum follicle-stimulating hormone
(FSH) concentrations.
 Concurrent administration of testosterone might protect against long-term
gonadal injury in adults.

Drugs
 Ketoconazole - The antifungal drug directly inhibits testosterone
biosynthesis, thereby causing testosterone deficiency .
 Glucocorticoids - Chronic glucocorticoid use can also lower
testosterone levels by about one-third; the mechanism is not clear,
but inhibition may occur at both the testis and pituitary.
Autoimmune Syndromes
 Anti-Leydig cell antibody-associated disorders or conditions
associated with anti-sperm antibodies are autoimmune syndromes
related to hypogonadism.
 The hypogonadism that accompanies autoimmune polyglandular
disease is also characterized by hypothyroidism and hypoadrenalism.

Trauma- Trauma to the testes can be sufficiently severe to
damage both seminiferous tubules and Leydig cells.
Testicular Torsion- Testicular torsion is one of the
most common reasons for the loss of a testicle before puberty.
- Testicular torsion is a twisting of the testis on the spermatic cord,
which results in acute loss of the blood supply to the testis.
- Torsion lasting more than eight hours can lead to sufficient
damage to the seminiferous tubules to lower the sperm count .
Bilateral Orchiectomy- Orchiectomy is standard
treatment for testicular cancer, which is often bilateral, although it
often occurs at different times on each side.

Chronic Systemic Diseases
 Many chronic, systemic illnesses cause hypogonadism
both by a direct testicular effect and by decreasing gonadotropin secretion.
 Cirrhosis , Chronic renal failure, HIV
Hemochromatosis
 Iron overload may lead to primary gonadal failure or hypothalamic-pituitary
dysfunction that results in secondary gonadal failure .
 The diagnosis is made in the setting of associated findings of hemochromatosis
in conjunction with an increased ferritin level.
Idiopathic
 Primary hypogonadism may be idiopathic, whether it is severe, resulting
in testosterone deficiency and azoospermia, or mild, resulting only in
oligospermia/azoospermia and an elevated FSH.

Laboratory Studies
A) Testosterone
 Testosterone concentrations may be affected by illness and certain medications (e.g.
opiates and glucocorticoids).
 Total testosterone concentrations are influenced by alterations in SHBG
concentrations.
 Serum testosterone levels exhibit a circadian variation with peak values in the
morning; this circadian rhythm is blunted with aging .
 Because of this circadian variation in testosterone levels & the fact that normal ranges
for serum testosterone are established using morning blood samples, testosterone
measurement for the diagnosis of androgen deficiency should be performed in the
morning.
 It is important to confirm low testosterone concentrations in men with an initial
testosterone level in the mildly hypogonadal range because 30% of such men may
have a normal testosterone level on repeat measurement .

 Also, 15% of healthy young men may have a testosterone level below the normal
range in a 24-h period (day-to-day variations)
 Single testosterone measurements were inadequate to characterize an individual’s
levels, and at least two testosterone measurements were needed to diagnose
androgen deficiency with greater confidence.
 Serum total testosterone concentration represents the sum of unbound and
protein-bound testosterone in circulation.
 Most of the circulating testosterone is bound to SHBG and to albumin ;only 0.5–3%
of circulating testosterone is unbound or “free. ”
 The term “bioavailable testosterone” refers to unbound testosterone plus
testosterone bound loosely to albumin.
 Free or bioavailable testosterone concentrations should be measured when total
testosterone concentrations are close to the lower limit of the normal range and
when altered SHBG levels are suspected, e.g. in older men and in men with obesity,
diabetes mellitus, chronic illness, or thyroid disease.
 https://www.ncbi.nlm.nih.gov/pubmed/20525905

B) Gonadotropins
 Both FSH and LH are secreted in short pulses.
 FSH has a longer half-life than does LH and is more likely to provide
adequate results on a single blood sample.
 Because LH has a shorter half-life than does FSH, errors may be introduced
in measurements made on single samples.
 Pooled samples for LH done 20 to 30 minutes apart are more accurate
than single-sample determinations (albeit less convenient).
 Persistent borderline values may be further evaluated with dynamic
endocrine testing.
 These tests may include the GnRH stimulation test, the clomiphene
stimulation test, and the human chorionic gonadotropin (hCG) stimulation
test.
 AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)

C) Semen Analysis
 A semen analysis is the primary test to assess the fertility potential of the
male patient.
 Semen should be collected by masturbation after 2 to 5 days of
abstinence and evaluated within 2 hours.
 Variability between specimens is common; with low or borderline
samples, follow-up consisting of evaluation of three or more samples
should be done during a 3-month period.
 A fructose test should be done on a semen sample showing
azoospermia.
 Because fructose is secreted by the seminal vesicles, absence of fructose
may indicate complete obstruction of the ejaculatory ducts or
congenital absence of both vasa deferens and both ejaculatory ducts.

D) Genetic Studies
 Patients with hypergonadotropic hypogonadism and impaired pubertal
development associated with small, firm testes and often with gynecomastia
are likely to have Klinefelter’s syndrome or a variant.
 Classically, a buccal smear was done to establish the diagnosis by revealing
Barr bodies.
 Genetic karyotype testing to confirm the diagnosis.
E) Testicular Biopsy and Scrotal Exploration
 Since the advent of sensitive FSH assays, germinal cell function is now
most often assessed through the FSH assay alone rather than testicular biopsy.
 Men with azoospermia, normal FSH levels, and normal testicular size should
usually undergo testicular biopsy and scrotal exploration to determine
whether a germinal cell abnormality, an obstruction, or a congenital
abnormality of the vasa is present.

Diagnosis
 It is recommended to make a diagnosis of androgen deficiency only in men with
consistent symptoms and signs and unequivocally low serum testosterone levels
between 8 and 10 AM on at least two occasions.
 If a single 8 to 10 AM value is well within the normal range, testosterone production
can be assumed to be normal.
 If a single 8 to 10 AM value is low or borderline low or does not fit with the clinical
findings, the measurement should be repeated once or twice before making the
diagnosis of hypogonadism.
 The normal range in adult men in most laboratories is about 300 to 800 ng/dL.
 Should confirm of the diagnosis by repeating measurement of total testosterone.
 Should measure free / bioavailable testosterone level, using an accurate & reliable
assay, in some men in whom total testosterone concentrations are near the lower limit
of the normal range and in whom alterations of SHBG are suspected.
 Evaluation of androgen deficiency shouldn’t be made during an acute/subacute illness.
 J Clin Endocrinol Metab, June 2010, 95(6):2536–2559

Testosterone Therapy
 Testosterone therapy for symptomatic men with classical androgen
deficiency syndromes aimed at inducing and maintaining secondary
sex characteristics and at improving their sexual function, sense of
well-being, and bone mineral density.
 When clinicians prescribe testosterone therapy, the therapeutic target
should be to raise serum testosterone levels into a range that is mid-
normal for healthy, young men.
 In men receiving testosterone enanthate or cypionate, serum
testosterone levels vary during the dosing interval ;
 Aiming for testosterone levels between 400 and 700 ng/dl midway
between injections.

Monitoring Men Receiving Testosterone Therapy
 Evaluate the patient 3 to 6 months after treatment initiation and then annually
to assess whether symptoms have responded to treatment and whether the
patient is suffering from any adverse effects.
 Monitor testosterone level 3 - 6 months after initiation of testosterone therapy:
 Therapy is aimed to raise serum testosterone level into the mid-normal range.
 1) Injectable testosterone enanthate or cypionate: measure serum
testosterone level midway between injections. If testosterone is 700 ng/dl (24.5
nmol/liter) or 400 ng/dl (14.1 nmol/liter), adjust dose or frequency.
 2) Transdermal patches: assess testosterone level 3–12 h after application of
the patch; adjust dose to achieve testosterone level in the mid-normal range.
 3) Buccal testosterone bio-adhesive tablet: assess level immediately before
or after application of fresh system.

 4) Transdermal gels: assess testosterone level any time after patient has been
on treatment for at least 1 week; adjust dose to achieve serum testosterone level in
the mid-normal range.
 5)Testosterone pellets: measure testosterone levels at the end of the dosing
interval. Adjust the number of pellets and/or the dosing interval to achieve serum
testosterone levels in the normal range.
 6) Oral testosterone undecanoatea: monitor serum testosterone level 3 to 5
h after ingestion.
 7) Injectable testosterone undecanoate: measure serum testosterone level
just prior to each subsequent injection and adjust the dosing interval to maintain
serum testosterone in mid-normal range.
 Check hematocrit at baseline, at 3 to 6 months, and then annually.
If hematocrit is 54%, stop therapy until hematocrit decreases to a safe level;
evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced
dose.

 Measure bone mineral density of lumbar spine and/or femoral neck
after 1–2 year of testosterone therapy in hypogonadal men with osteoporosis or
low trauma fracture, consistent with regional standard of care.
 In men 40 year of age or older with baseline PSA greater than 0.6 ng/ml,
perform digital rectal examination and check PSA level before initiating
treatment, at 3 to 6 months, and then in accordance with guidelines for prostate
cancer screening depending on the age and race of the patient.
 Obtain urological consultation if there is:
 An increase in serum PSA concentration 1.4 ng/ml within any 12-
month period of testosterone treatment.
 A PSA velocity of 0.4 ng/ml yr using the PSA level after 6
months of testosterone administration as the reference (only
applicable if PSA data are available for a period exceeding 2 yr).
 Detection of a prostatic abnormality on digital rectal examination.
 An AUA/IPSS of 19.

Testosterone Therapy in Men with Sexual Dysfunction
 Offer testosterone therapy to men with low testosterone levels and low libido to improve
libido and to men with ED who have low testosterone levels after evaluation of underlying
causes of ED and consideration of established therapies for ED.
HIV-Infected Men with Weight Loss
 Consider short-term testosterone therapy as an adjunctive therapy in HIV-infected men with
low testosterone levels and weight loss to promote weight maintenance and gains in LBM
and muscle strength.
Glucocorticoid-Treated Men
 Offer testosterone therapy to men receiving high doses of glucocorticoids who have low
testosterone levels to promote preservation of LBM and bone mineral density.
 Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol
Metab, June 2010, 95(6):2536–2559

Time Course of Effects
The time course of the effects of testosterone replacement is variable.
Increases in fat-free mass, prostate volume, erythropoiesis, energy, and sexual
function occurred within the first three to six months.
In contrast, the full effect on bone mineral density (BMD) did not occur until 24
months.
In general, the benefits of TRT are more consistent in men with very low testosterone
concentrations than in those with concentrations just below the normal range.
Health care professionals should make patients aware of the possible increased
cardiovascular risk when deciding whether to start or continue a patient on
testosterone therapy.
TRT should not be provided to men who have untreated or metastatic prostate
cancer or breast cancer.
 Testosterone and Cardiovascular Risk, Endocr Prac. 2015;21(No. 9)

Relative Contraindications
 Untreated severe sleep apnea,
 A hematocrit >50%,
 Severe lower urinary tract symptoms with an International
Prostate Symptom Score above 19,
 Uncontrolled or poorly controlled heart failure,
 A MI or cerebrovascular accident within the past 6 months,
 A personal or family history of a pro-coagulant state,
 A personal history of thromboembolism
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