Dr. James Manos (MD)
January 5, 2016
Review: Tips in Medical Biochemistry
Volume (2)
CONTENTS
Testosterone
Male hypogonadism
Causes of male hypogonadism
Diagnostic approach of male hypogonadism
Diagnostic algorithm for low testosterone (male hypogonadism):
Diagnostic algorithm for male hypogonadism
Amenorrhea
Causes of amenorrhea
Workup of primary and secondary amenorrhea
Diagnostic algorithm for primary amenorrhea
Diagnostic algorithm for secondary amenorrhea
Diagnostic algorithm – evaluation of primary amenorrhea
Diagnostic algorithm – evaluation of secondary amenorrhea
Testosterone
· Testosterone:
· Much of the testosterone in the blood is bound to the protein called sex hormone-binding globulin (SHBG).
· Blood samples for testosterone should be taken between 7 – 10 a.m.
· ''Free testosterone'' can also be measured.
· In males, the testicles produce most of the testosterone. Testosterone in men is checked usually to evaluate signs of low testosterone in men such as early or late puberty on boys; infertility; erectile dysfunction; low libido; osteoporosis (in men).
· In females, the ovaries produce most of the testosterone. The adrenal glands also produce other androgens that are converted to testosterone. Testosterone in women is checked to evaluate signs of high testosterone levels in females such as acne, oily skin; change in voice (deepening); decreased breast size; excess hair growth (thick dark hair in the area of the mustache, beards, sideburns, chest, buttocks, inner thighs); increased size of the clitoris; irregular or absent menstrual periods; male – pattern baldness or hair thinning.
· Causes of increased testosterone: resistance to the action of male hormones (androgen resistance); tumor of the ovaries; cancer of the testes; congenital adrenal hyperplasia; medications or drugs that increase testosterone levels.
· Causes of decreased testosterone: chronic illness, a condition in which the pituitary gland does not produce normal amounts of some or all of its hormones, injury or disease of the hypothalamus, delayed puberty, disorders of the testicles (trauma, infection, immune), noncancerous tumor of the pituitary cells that produce too much of the hormone prolactin (prolactinoma).
Male hypogonadism
· Male hypogonadism: hypogonadism can begin during fetal development, before puberty, or during adulthood.
· a) Fetal development/ birth/ infancy: If the body doesn't produce enough testosterone during fetal development, the result may be the impaired growth of the external sex organs. Depending on when hypogonadism develops and how much testosterone is present, a child who is genetically male may be born with: female genitals, ambiguous genitals (that are neither distinctly male nor distinctly female), and underdeveloped male genitals. The persistent failure of the testes to descend may be an early manifestation of testicular dysfunction. Also, a normally formed but hypotrophic penis may provide a clue to an abnormality of the hypothalamic-pituitary-gonadal axis.
· b) Puberty: Male hypogonadism may delay puberty or cause incomplete or lack of normal development. It can cause a decreased development of muscle mass, lack of deepening of the voice, impaired growth of body hair, impaired growth of the penis and testicles, excessive growth of the arms and legs concerning the trunk of the body, and gynecomastia (development of breast tissue). Delayed, arrested, or absent testicular growth and secondary sexual characteristic development are hallmarks of pubertal disorders. Skeletal proportions may be abnormal (eunuchoid) with more than a 5-cm difference between span and height and between pubis-floor and pubis-vertex dimensions.
· c) Adulthood: in adult males, hypogonadism may alter specific masculine physical characteristics and impair normal reproductive function. Signs and symptoms may include erectile dysfunction, infertility, a decrease in beard and body hair growth, reduction in muscle mass, gynecomastia (development of breast tissue), and osteoporosis. Hypogonadism can also cause mental and emotional changes. As testosterone decreases, some men may experience symptoms similar to those of menopause in women that may include (andropause): fatigue, decreased libido (decreased sex drive), difficulty concentrating, and hot flashes. Manifestations in adults are generally more subtle. Prolactin excess, testosterone deficiency, or both in men may result in impaired libido and erectile dysfunction. The yield of finding hyperprolactinemia or testosterone deficiency, or both, in patients presenting with these symptoms, is generally considered to be low, usually less than 5%. However, an extensive survey of patients with erectile dysfunction presenting to a Veterans Affairs center has suggested that the prevalence of these abnormalities is substantial: 18.7% of patients with low testosterone levels and 4.6% with elevated prolactin levels. The first manifestation of hypogonadism may be a consequence of a large space-occupying intrasellar or para sellar lesion of the brain manifested by headaches, bitemporal hemianopia, or extraocular muscle palsy. Galactorrhea as a manifestation of hyperprolactinemia is rare but rarely sought. Unexplained osteoporosis or mild anemia sometimes is the clue to an underlying hypogonadal state.
· Causes of male hypogonadism:
· a) Primary (hypergonadotropic) hypogonadism – major causes: genetic (Klinefelter’s syndrome); congenital (anorchia); toxins (alcohol, heavy metals); orchitis; trauma; infarction; aging.
· b) Secondary (hypogonadotropic) hypogonadism – major causes: pubertal delay; congenital or acquired; space-occupying lesions of pituitary or hypothalamus; infiltrative, infectious; sex steroids; aging (?); hypogonadotropism; isolated or combined pituitary disease; hyperprolactinemia; suppression; GnRH (gonadotropin-releasing hormone) analogs.
· Conditions associated with male hypogonadism: aging; chronic illness; diabetes mellitus; chronic renal failure; cancer cachexia; corticosteroid use; rheumatoid arthritis (RA); AIDS etc.
· Diagnostic approach of male hypogonadism: because of the well-known diurnal rhythm of serum testosterone excretion, which appears to be lost with age (>60 years), with values 30% or so higher near 8 am versus the later day trough, a testosterone value should be determined first thing in the morning. Normal ranges vary among laboratories. Although the usually quoted range for young men is 300 – 1000 ng/dL. In general, values below 220 – 250 ng/dL are distinctly low in most laboratories; values between 250 and 350 ng/dL should be considered borderline low. Because the acute effect of stressful illness may result in a transient lowering of testosterone levels, a confirmatory early morning specimen should be obtained.
· Measurement of free testosterone levels or bioavailable testosterone levels may provide additional information. For example, free testosterone levels may be lower than expected from the total testosterone level as a result of aging and higher than anticipated in insulin-resistant individuals, such as in obesity.
· Also, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) levels should be determined to help delineate the cause of the testosterone-deficient state.
· If gonadotropin (FSH, LH) levels are not elevated, despite clearly subnormal testosterone values, anterior pituitary (thyroid-adrenal) function should be determined by measuring free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, as well as an early morning cortisol level.
· An MRI scan of the brain (focusing especially on the sella) should be considered. An exception to this recommendation is the condition of morbid obesity, in which both total and free testosterone levels are typically low and gonadotropin values are not elevated.
· Hyperprolactinemia, even of a small degree, may also warrant ordering a brain MRI, because interference of hypothalamic-pituitary vascular flow by space-occupying, stalk-compressing lesions will lead to disruption of the tonic inhibitory influence of hypothalamic dopamine, and result in modest hyperprolactinemia (usually 20 to 50 ng/mL range).
· Note: a semen analysis should be performed when fertility is in question.
· Diagnostic algorithm for low testosterone (male hypogonadism):
· http://www.primaryissues.org/pi-images/Articles/CME_Testosterone%20Deficiency/TRT-F6sn.jpg (T= testosterone; TRT= testosterone replacement therapy)
· Diagnostic algorithm for male hypogonadism:
Amenorrhea
· Amenorrhea is the absence of a menstrual period in a woman of reproductive age.
· Primary amenorrhea is the failure of menses to occur by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 13 menses have not happened and the onset of puberty, such as breast development, is absent, a workup for primary amenorrhea should start.
· Secondary amenorrhea is defined as the cessation of menses sometime after menarche has occurred.
· Oligomenorrhea is defined as menses occurring at intervals longer than 35 days apart.
· Primary amenorrhea, which by definition is a failure to reach menarche, is often the result of chromosomal irregularities leading to primary ovarian insufficiency (e.g., Turner syndrome) or anatomic abnormalities (e.g., Müllerian agenesis).
· In patients with primary amenorrhea, the presence or absence of sexual development should direct the evaluation.
· Constitutional delay of growth and puberty commonly causes primary amenorrhea in patients with no sexual development.
· If the patient has normal pubertal development and a uterus, the most common etiology is congenital outflow tract obstruction with a transverse vaginal septum or imperforate hymen.
· If the patient has abnormal uterine development, Mullerian agenesis is the likely cause, and a karyotype analysis should confirm that the patient is 46, XX.
· Secondary amenorrhea is defined as the cessation of regular menses for three months or the termination of irregular menses for six months. Most cases of secondary amenorrhea can be attributed to polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, hyperprolactinemia, or primary ovarian insufficiency.
· Pregnancy should be excluded in all cases.
· Causes of amenorrhea:
· I) Hyperprolactinemia:
· a) Prolactin ≤ 100 ng/ mL (100 mcg/ L)):
· i) Altered metabolism: liver failure, renal failure.
· ii) Ectopic production: bronchogenic (e.g., carcinoma), gonadoblastoma, hypopharynx, ovarian dermoid cyst, renal cell carcinoma, teratoma.
· iii) Breastfeeding.
· iv) Breast stimulation.
· v) Hypothyroidism.
· vi) Medications: oral contraceptive pills, antipsychotics, antidepressants, antihypertensives, histamine H2 receptor blockers, opiates, cocaine.
· b) Prolactin > 100 ng/ ml:
· i) Empty Sella syndrome.
· ii) Pituitary adenoma.
· II) Hypergonadotropic hypogonadism:
· a) Gonadal dysgenesis: Τurner’s syndrome (*); other (*)
· b) Postmenopausal ovarian failure.
· c) Premature ovarian failure: autoimmune; chemotherapy; galactosemia; genetic; 17-hydroxylase deficiency syndrome; idiopathic; mumps; pelvic radiation.
· III) Hypogonadotropic hypogonadism: anorexia or bulimia nervosa; CNS (central nervous system) tumor; constitutional delay of growth and puberty (*); chronic illness (chronic liver disease, chronic renal insufficiency, diabetes, immunodeficiency; inflammatory bowel disease, thyroid disease, severe depression or psychosocial stressors), cranial radiation, excessive exercise, excessive weight loss or malnutrition, hypothalamic or pituitary destruction, Kallmann syndrome (*) (failure to start puberty or failure to fully complete it; it occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility; also features the additional symptom of an altered sense of smell as hyposmia or anosmia), Sheehan’s syndrome (hypopituitarism caused by ischemic necrosis due to blood loss and hypovolemic shock during and after childbirth).
· IV) Normogonadotropic:
· a) Congenital: androgen insensitivity syndrome (*), Müllerian agenesis (*).
· b) Hyperandrogenic anovulation: acromegaly, androgen-secreting tumor (ovarian or adrenal), Cushing’s disease, exogenous androgens, nonclassic congenital adrenal hyperplasia, polycystic ovary syndrome (PCOS), thyroid disease.
· c) Outflow tract obstruction: Asherman’s syndrome (also called Fritsch syndrome; a condition characterized by adhesions and/or fibrosis of the endometrium most often associated with dilation and curettage of the intrauterine cavity), cervical stenosis, imperforate hymen (*), transverse vaginal septum (*).
· V) Other: pregnancy; thyroid disease.
· (*) Causes of primary amenorrhea only.
· Workup of primary and secondary amenorrhea: initial workup includes a pregnancy test and serum levels of LH (luteinizing hormone), FSH (follicle-stimulating hormone), PRL (prolactin), and TSH (thyroid-stimulating hormone).
· If hirsutism is predominant upon examination, the workup should include androgen testing: testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17-OH progesterone to determine the organ of the cause (e.g., adrenal gland vs. ovary).
· If the history or physical findings suggest a chronic disease process, indicated tests may include erythrocyte sedimentation rate (ESR), liver function tests (LFTs), blood urea nitrogen (BUN), creatinine determination, and urinalysis.
· If the history and physical findings suggest a delay in puberty, assessing FSH and LH levels and determining bone age are essential in differentiating pubertal delays as a cause.
· Secondary amenorrhea: pregnancy is the most common cause of secondary amenorrhea. A pregnancy test (measurement of serum or urinary human chorionic gonadotropin) is recommended as the first step in the evaluation of secondary amenorrhea.
· After pregnancy testing, all women who present with 3 months of secondary amenorrhea should have a diagnostic assessment initiated at that visit.
· A complete blood cell count (CBC, FBC), urinalysis, and serum chemistries should be evaluated to help rule out systemic disease. Serum prolactin (PRL), FSH, estradiol, and thyrotropin (thyroid-stimulating hormone (TSH)) levels should also be measured routinely in the initial evaluation of amenorrhea once pregnancy has been excluded.
· In the future, the determination of anti-mullerian hormone levels may become the preferred initial test for diagnosing PCOS (polycystic ovary syndrome) and also to assess premature ovarian failure.
· Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs.
· MRI can detect hypothalamic/pituitary lesions.
· Hysterosalpingography and hysteroscopy are indicated in cases of possible Asherman syndrome.
· Diagnostic algorithm for primary amenorrhea:
· Diagnostic algorithm for secondary amenorrhea:
· Diagnostic algorithm – evaluation of primary amenorrhea:
· Diagnostic algorithm – evaluation of secondary amenorrhea:
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