Male Gonadal Dysfunction R. Dale Childress, M.D., FACE

Gonadal Disorders-Objectives Understand the hypothalamic-pituitary-gonadal axis primary versus secondary hypogonadism Become familiar with the etiologic categories of testicular endocrine disorders Learn appropriate diagnostic evaluation and interpretation of laboratory results of patients with these disorders

The Hypothalamic-Pituitary-Gonadal Axis

GnRH Decapaptide  Pulsatile release 90-120 minute cycles  Plasma half-life 2-5 minutes  High concentration in hypothalamicpituitary portal system  Pulsatile stimulation triggers release of LH and FSH 

LH and FSH Glycopeptides consisting of two chains (alpha and beta)  Alpha subunit is shared with TSH and hCG  LH stimulates testosterone production in Leydig cells  FSH stimulates and maintains spermatogenesis 

Testicular peptide hormones Follistatin inhibits activins and inhibins  Activins 

 



Produced in Sertoli cells Stimulate FSH beta-subunit production

Inhibins   

Produced in seminiferous tubules and Sertoli cells Suppresses FSH secretion Injury to seminiferous tubules leads to elevated FSH

Primary vs. Secondary 

By definition, primary hypogonadism is failure of the testes



Secondary hypogonadism is any nontesticular condition including hypothalamic and pituitary diseases

Defects by anatomical site of primary defect 

Hypothalamic disorders- low GnRH leads to failed LH and FSH production



Pituitary disorders- low LH and/or FSH production leads to failed testosterone production and/or spermatogenesis



Gonadal disorders- failure of testosterone production from Leydig cells and/or spermatogenesis, no feedback leads to elevated LH and FSH



Post-gonadal disorders

Hypothalamic disease Inappropriately ‘normal’ LH and FSH with low testosterone

Kallman’s Syndrome- anosmia Prader-Willi Syndrome- obesity, hypotonia, micropenis, small hands and feet

Lawrence-Moon Syndrome- retinitis pigmentosa polydactyly

Pituitary Disease Inappropriately ‘normal’ LH and FSH with low testosterone

Fertile Eunuch Syndrome- LH deficiency Isolated FSH Deficiency Hyperprolactinemia- inhibited GnRH release and libido

Hemochromatosis- loss of LH and FSH (also effects testes directly and can cause a primary hypogonadism)

Testicular Diseases High LH and FSH due to absent feedback of testosterone

Bilateral Anorchia (Vanishing Testes Syndrome) Cryptorchidism Sertoli Cell Only Syndrome Myotonic Dystrophy Gonadotoxins Cytotoxic Chemotherapy Radiation Orchitis Systemic Illness Hemochromatosis

“Post-testicular” Disorders Exogenous Hormones- tonic inhibition of GnRH and LH/FSH production

Estrogen Excess- tonic inhibition of GnRH and LH/FSH production and permissive increase in prolactin

Androgen Insensitivity- normal testosterone, LH, FSH, female phenotype (formerly known as testicular feminization)

Chromosomal Disorders Klinefelter’s (XXY) Syndrome- tall, gynecomastia, eunuchoid habitus, MR common

XYY- oligo/azospermia Noonan’s Syndrome (XO)- phenotypically similar to Turner’s patients

XX Male Syndrome- normal height, no MR, azospermia

Pre-pubertal Gonadal Failure • Small testes, phallus, and prostate • Delayed puberty • Scant pubic and axillary hair • Disproportionately long arms and legs (from delayed epiphyseal closure) • Reduced male musculature • Gynecomastia • Persistently high-pitched voice

Post-pubertal Gonadal Failure • Progressive decrease in muscle mass • Loss of libido • Impotence • Oligospermia or azoospermia • Occasionally, menopausal-type hot flushes (with acute onset of hypogonadism) • Poor ability to concentrate

Evaluation of the hypogonadal patient History Family Fertility status Physical exam arm span to height axillary and pubic hair phallus and testes Laboratory Testosterone FSH LH Prolactin Karyotyping Provocative testing GnRH stimulation Clomiphene stimulation hCG stimulation Pituitary MRI

Lab evaluation Testosterone  FSH  LH  Prolactin 

Testosterone     

  

Levels vary from hour to hour Normally highest levels in the early morning hours Circulates bound to sex hormone-binding globulin (SHBG) and albumin Only ~2% of total hormone is truly free for biological availability Normal total testosterone can be seen in hypogonadal patients with increased SHBG in whom the available testosterone is truly low SHBG increase about 1% per year with aging Equilibrium dialysis measures of free testosterone are most accurate Low SHBG can be seen with hypothyroidism, acromegaly and obesity

Gonadotropins LH and FSH are both released in a pulsatile fashion  LH has a shorter plasma half-life than FSH and single low measures may be misleading 



Biologic activity is affected by post-translational glycosylation and 2-site radioimmunometric assays yield results which correlate well with biologic activity.

GnRH Stimulation Test In the GnRH stimulation test, intravenous injection of 100 μg of GnRH causes serum LH levels to increase threefold to sixfold during a period of 30 to 45 minutes and FSH levels to increase between 20 and 50%. Various degrees of primary testicular failure cause higher than expected peak values for LH and FSH. Men with hypothalamic or pituitary disease may have a reduced or normal response that is often inadequate for distinguishing between a pituitary and a hypothalamic disorder. If the pituitary gland is primed with repeated doses of GnRH, this stimulation test may provide a more sensitive and reliable result.

Clomiphene Stimulation Test 100 mg of clomiphene citrate is given for 5 to 7 days as an evocative test of the hypothalamic-pituitary axis Clomiphene acts by interrupting the negative feedback loop and thereby stimulating release of gonadotropins from the pituitary A doubling of LH and a 20 to 50% increase in FSH are normal results indicative of an intact hypothalamicpituitary response

hCG Stimulation Test Various protocols are used for hCG stimulation testing. In general for postpubertal male patients, a single dose of hCG (5,000 IU intramuscularly) is administered Pre-therapy and 72-hour post-therapy testosterone measurements are obtained (some protocols use 1,000 to 4,000 IU of hCG or multiday dosing)

Semen Analysis A semen analysis is the primary test to assess the fertility potential of the male patient. Semen should be collected after 2 to 5 days of abstinence and evaluated within 2 hours. A fertile sample is usually associated with a motility of more than 50% and a sperm count that exceeds 20 million/mL. In general, semen volume should range from 1.5 to 6 mL. Morphologic features should be examined for abnormalities. 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

Summary 







Normal regulation of the hypothalamic-pituitary-testicular axis requires pulsatile GnRH release, pulsatile LH and FSH release and intact Leydig and Sertoli cell function Both heritable disorders of development and function as well as acquired insult to these regions produce defects in hormone and sperm production Hormones which drive production of a hormone the body can no longer make will be present at higher-than-normal levels allowing the use of measurement of LH and FSH to aid in determining the anatomic lesion responsible for hypogonadism Low or inappropriately normal LH and FSH in the face of low testosterone are the hallmark of hypothalamic and pituitary defects , while elevated LH and FSH are seen in the face of testicular failure

Thank you for your attention! Questions?