Handbook of Diagnostic Endocrinology - part 9 ppsx

A more straightforwardapproach is to base classification on gonadotropin levels: those associated withlow or normal LH and/or FSH hypogonadotropic hypogonadism suggests aproblem at the l

B together regulate spermatogenesis in the presence of high intratesticular

levels of testosterone (4) Testosterone is a prohormone and is converted by 5reductase to dihydrotestosterone, a more potent androgen, or by aromatase intoestradiol Although androgens were thought to be the major sex steroid hormone

α-in men, recent studies α-in animals and humans without an estrogen receptor(ERα) suggest that estradiol plays a critical role in normal spermatogenesis and

hormone feedback in the male (5,6) LH levels are controlled primarily by

GnRH from the hypothalamus and negative feedback from testosterone and

estradiol from the testes (7–9) FSH levels, in contrast, are controlled by GnRH,

gonadal steroid hormone feedback and the actions of the gonadal peptides,inhibin B, activin A, and follistatin derived from both the gonad and the pituitary

(10) A critical feature of this endocrine system is the negative feedback of

steroid hormones on hypothalamic and pituitary hormone production (2) tosterone levels are secreted in a circadian rhythm with increases at night (3).

Tes-Another feature is the requirement for an episodic pattern of hormone secretion

for normal reproductive function (1–3) Continuous production of

GnRH-induced LH secretion turns off the system and is the basis for GnRH analoguesused as reversible medical castration in hormone-dependent malignancies such

as prostate cancer This episodic pattern of hormonal signaling is important toremember when obtaining samples for hormone levels

Fig 1 Diagram of the hypothalamic-pituitary-testicular axis GnRH from

hypotha-lamic neurons activates the gonadotropin subunit genes ( α, LHβ, FSHβ) to release LH and FSH from the pituitary These in turn stimulate spermatogenesis and production of sex steroids (testosterone, estradiol) and the gonadal peptide, inhibin B.

Table 1 Classification of Erectile Dysfunction

VascularNeurogenicPsychogenicIatrogenicHormonal (hypogonadism)

NORMAL PHYSIOLOGY OF ERECTION

There are two critical events during erection Dilation of the arterial bed withdecreased resistance to allow increased blood flow is coupled with relaxation of the

trabecular smooth muscle to compress the venous outflow (11,12) The cavernosal

relaxation is mediated by adrenergic receptors activated by norepinephrinereleased from sympathetic nerves The autonomic nerves, once thought to be theprimary control system, are now thought to act as modulators of the sympatheticactivation to maintain flaccidity Instead, it is the nonadrenergic, noncholinergic

system that mediates erection (13,14) Nitric oxide (NO) is released both from

the endothelium and the local nerve endings in the corpora cavernosa to triggersmooth muscle relaxation via activation of guanylate cyclase and the genera-

tion of cyclic guanine monophosphate (cGMP), resulting in an erection (15).

The components of the normal physiology are relevant to the new treatmentoptions for erectile dysfunction and for those under active investigation

CLASSIFICATION OF ERECTILE DYSFUNCTION

Erectile dysfunction is defined as the inability to achieve or maintain erection

sufficient to permit satisfactory intercourse (16) The prevalence of this disorder

increases with age and with associated co-morbidities, such as diabetes,

athero-sclerosis, hyperlipidemia, or hypertension (17) Impotence can be generally

clas-sified into five categories: vascular, neurogenic, psychogenic, iatrogenic (due to

a medication the physician prescribes or the patient takes), or hormonal (Table 1)

By the time a patient presents for evaluation, he usually, if not always, hasmultifactorial erectile dysfunction Table 2 outlines the strategy for evaluation

Vascular

Associated vascular disease is the most common underlying etiology of

patients presenting with impotence and occurs in up to 40% of men (16,17).

Arterial insufficiency results in impaired blood flow to the cavernosal muscles

A careful history and physical examination can detect the presence of macro- ormicrovascular disease A history of hypertension, hyperlipidemia, or diabetespredicts an underlying vascular component to erectile dysfunction

Both trauma, such as spinal cord injury, or systemic diseases, such as diabetes

or primary neurologic diseases, impair the normal process of erection (16–19).

Disorders that impact on the adrenergic, sympathetic, or nonadrenergic cholinergic NO system all result in erectile dysfunction Additionally, radical pros-tatectomy, pelvic irradiation, and disorders that cause a peripheral neuropathy,

non-such as toxins and alcohol are associated with impotence (16–19).

Psychogenic

By the time a patient presents to a health care professional for evaluation oferectile dysfunction, there is almost uniformly a psychogenic component to the

process (16–19) Performance anxiety can play a role with underlying normal

sexual functioning An acute onset of impotence associated with a major lifestressor is a clue for a predominant psychogenic etiology Patients with underly-ing primary psychoses or neuroses often have decreased libido and erectile dys-function when their disease is poorly controlled In addition, medications given

to treat the psychiatric illness are associated with similar symptoms making theunderlying trigger often difficult to clarify

Iatrogenic

Iatrogenic refers to ingestion of compounds or drugs by the patient scribed by a physician or taken on their own that impair erectile function

pre-(11,12,18,19) These include antihypertensive medications such as diuretics,

β-blockers, and verapamil Anti-androgens such as cimetidine, flutamide, andspironolactone can cause gynecomastia and impotence Most psychiatric medi-cations affect libido, elevate prolactin, and can cause hypogonadism as well aserectile dysfunction Some over-the-counter medications, including herbal andhealth food products, cause impotence, although the exact mechanism has notbeen elucidated It is important to review all medications, vitamins, or healthproducts with each patient

Table 2 Approach to the Patient with Impotence

Complete historyReview of medicationsCareful physical examinationLaboratory:

LH, FSH, testosterone +/– prolactin, TSHGlucose

Lipid profileLiver function tests

Previously, it was argued that hypogonadism is a rare cause of erectile

dysfunction, occurring in less than 10% of men (16,17,19,20) However, these

studies were conducted in urological practices that included younger men withpredominantly psychogenic etiologies With the renewed interest in erectiledysfunction by primary care physicians, the educational programs available tothe patients, and new treatment options, the number of patients presenting with

a hormonal component to their erectile dysfunction is increasing We performed

a retrospective review of hormonal measurements in patients presenting to ourImpotence Clinic at the Denver VA Medical Center and found that 48% had some

endocrine abnormality contributing to their erectile dysfunction (21) Thus, it is

our practice to exclude hypogonadism as a contributing factor in all men ing with impotence Similarly, Buvat and coworkers suggest screening with a

present-testosterone and prolactin level (22) A discussion of the differential diagnosis

of patients presenting with hypogonadism is given below

CLASSIFICATION OF MALE HYPOGONADISM

There are several ways to classify hypogonadism Many have used primaryand secondary to refer to defects at the level of the testes or central loci How-ever, this classification is confusing, since congenital and acquired disorderscan also be thought of as primary and secondary A more straightforwardapproach is to base classification on gonadotropin levels: those associated withlow or normal LH and/or FSH (hypogonadotropic hypogonadism) suggests aproblem at the level of the brain or pituitary; high LH and/or FSH (hyper-gonadotropic hypogonadism) suggests a testicular problem The disorders canthen be divided into whether they are inherited or acquired In addition, one canask whether the defect is mechanical or hormonal The approach to disorders ofmale hypogonadism is presented in Tables 3 and the classifications of suchdisorders in Tables 4 and 5

Table 3 Approach to the Patient with Hypogonadism

Complete historyReview of medicationsCareful physical examinationLaboratory:

LH, FSH, testosteroneProlactin, thyroid function panel, free α-subunit,insulin-like growth factor (IGF)-1, cortisol

MRI if hypothalamic or pituitary disorderKaryotype if suspected Klinefelter’s, or genetic screening if familial

Hypogonadotropic Hypogonadism: Low or Normal LH and/or FSH and Low Testosterone (Table 4)

H YPOTHALAMIC D ISORDERS

Congenital GnRH Deficiency GnRH deficiency or idiopathic tropic hypogonadism is a disorder of the GnRH pulse generator (3) It occurs in1/10,000 men and 1/80,000 women (23) The disorder can occur in an X-linked,autosomal dominant, autosomal recessive, and sporadic fashion The patientpresents with a failure to undergo sexual maturation Patients with associatedmidline defects and anosmia are said to have Kallmann’s syndrome (24).Although one might expect the disorder to be due to a mutation in the GnRH gene,attempts to identify patients with mutations in the gene have been unsuccessful(25) Developmental biologists were the first to provide a clue to the underlyingdefect They showed that the GnRH neuronal population is born in the olfactoryplacode, and the cells must migrate across the cribiform plate into the forebrainand the hypothalamus during development (26) Investigators have shown that

hypogonado-the X-linked form of Kallmann’s syndrome is due to a mutation in hypogonado-the KAL gene

whose product has structural features of a neuronal cell adhesion molecule (26–29) An understanding of the exact physiologic role of the KAL protein has beenhampered by the fact that the gene is not expressed in rodents (29) Efforts areunderway to identify additional molecules that are important in the neuronalmigration of the GnRH population that may be miss-expressed in patients withother more common forms of GnRH deficiency syndrome

Other hypothalamic disorders are associated with hypogonadism Theseinclude Prader-Willi, in which patients have hyperphagia, morbid obesity, and

obstructive sleep apnea (30) Similarly, acquired obesity can be associated with hypoventilation and hypogonadism (31,32).

The rare disorder X-linked adrenal hypoplasia, caused by mutations in the

DAX-1 gene is associated with hypogonadotropic hypogonadism as well as

adrenal insufficiency (33,34) Studies in a mouse model suggest the primary

Table 4 Causes of Hypogonadotropic Hypogonadism

Hypothalamic disorders:

Congenital GnRH deficiencyAcquired GnRH deficiencyTumors of the hypothalamus: craniopharyngiomas, dysgerminomasPituitary disorders:

Genetic mutations in the GnRH receptor or gonadotropin subunit genesPituitary tumors: prolactin, adrenocorticotrophic hormone (ACTH), growth hormone (GH)

Infiltrative diseases of the pituitary: hemachromatosis, sarcoid

defect is in the control of secretion of GnRH, since gonadotropin synthesis and

secretion was restored with exogenous GnRH administration (35).

Acquired GnRH Deficiency Acquired GnRH deficiency may occur after

radiation or surgery to the hypothalamus (36,37) The hypothalamus is more

sensitive to the effects of radiation than the pituitary, and thus, patients we havepreviously labeled as having panhypopituitarism after radiation, often have theirdefect at the level of the hypothalamus The patients have multiple hypothalamicdefects resulting in multiple pituitary deficiencies and require lifelong hormonereplacement

Alternatively, men can have acquired defects in the GnRH pulse generator.Although hypothalamic amenorrhea is a well-recognized disorder in women due

to the effects of stress, excessive exercise, or eating disorders to inhibit normalreproductive function, it was previously thought to be rare in men This wasbased on the fact that GnRH-induced LH pulse frequency of every 2 h is fairlystable in men in contrast to the need for a changing hypothalamic input in the

female to maintain normal cyclicity (3) Recent studies however, have

docu-mented the acute reversible alteration in GnRH-induced gonadotropin secretion

in men with severe stress or with illness (38,39) Additionally, Nachtigall,

Crowley and coworkers reported a nonreversible type of acquired GnRH

defi-ciency in men (40) They studied a group of men who had undergone a normal

puberty, but then experienced loss of GnRH-induced gonadotropin secretion.Several clinical and biochemical features identified men with this disorder Theseincluded: higher testicular vol (18 vs 3 mL), higher baseline serum testosterone

level (78 vs 49 ng/dL), and higher serum inhibin B (119 vs 60 pg/mL) (40).

Tumors of the Hypothalamus Craniopharyngiomas are tumors that are

located at the level of the hypothalamus and pituitary Patients may present at any

age with partial or complete pituitary insufficiency (41) The patients often have

associated hyperprolactinemia and, depending on the timing of the development

of the tumor, can present with delayed or incomplete puberty or acquiredhypogonadism Patients with dysgerminomas or harmartomas of the hypothala-mus or pineal gland may present with either precocious sexual development or

acquired hypogonadism (42).

P ITUITARY D ISORDERS

Defective GnRH Receptor or Gonadotropin Subunit Gene Expression It

has recently been appreciated that there are genetic disorders that cause defects

in the reproductive axis, in addition to those associated with GnRH deficiency

A family has been described with mutations in the first and third intracellular

loop of the GnRH receptor gene (43) The brother and sister presented with

hypogonadotropic hypogonadism and delayed or absent puberty A homozygousmutation in the LH β-subunit gene has also been reported to cause male hypogo-

nadism (44), and several women with delayed puberty and hypogonadism have

been described with mutations in the FSH β-subunit gene (45,46).

Pituitary Tumors Tumors of the pituitary cause hypogonadism by either

mass effect and destruction of gonadotropes or by hormonal production, whichinhibits the GnRH pulse generator The most common type of pituitary tumor is

the prolactinoma, which occurs in 40% of patients (47) Although in men, the

tumors tend to be macroadenomas (greater than 1 cm in diameter), the nism of decreased testosterone levels is not by mass effect Instead, prolactin acts

mecha-at all levels of the hypothalamic-pituitary-testicular axis to inhibit function ies in hyperprolactinemic men showed that exogenous GnRH administration

Stud-with a GnRH pump induced normal reproductive function (48) These studies

confirm that the major effect of excess prolactin is at the level of the mus Recent studies have shown the presence of prolactin receptors on GnRHneuronal cell lines, consistent with the direct effects of prolactin on the GnRHpulse generator Prolactin has an independent effect on libido that is poorlyunderstood Thus, men given testosterone replacement for hypogonadism asso-ciated with a prolactinoma often will have persistent decreased libido until theprolactin level is normalized

hypothala-Other pituitary tumors are often present in men with hypogonadism Cushing’ssyndrome, with excess cortisol production from an endogenous or exoge-nous source, results in inhibition of the reproductive axis Again, the effects of

excess cortisol are to suppress GnRH secretion and induce hypogonadism (49,50).

Patients with acromegaly and growth hormone-producing tumors often havedecreased testosterone levels These patients usually have large tumors, so thatthe effects may be due to mass effect or may due to the fact that the tumors

co-secrete prolactin (51) Finally, patients with glycoprotein-secreting pituitary

tumors frequently have associated erectile dysfunction and hypogonadism, butwith elevated gonadotropins This will be discussed in further detail below

Infiltrative Diseases of the Pituitary There are many uncommon disorders

that involve infiltration of the pituitary and gonadotropin deficiency The mostcommon of these is hemachromatosis, in which excess iron is deposited selectively

in gonadotropes (52,53) The carrier frequency is 1/250, and the heterozygote can

present with the constellation of clinical features when exposed to excess hol These include severe hypogonadism with prepubertal testosterone levels, loss

alco-of body hair, diabetes, bronze discoloration alco-of the skin, cardiomyopathy and opathy, in addition to progressive liver disease and cirrhosis Aggressive phle-botomy is occasionally associated with reversal of the features early in the disease

arthr-process (53,54) Delayed diagnosis requires life-long androgen replacement.

Other diseases that infiltrate the pituitary and cause hypogonadism include the

granulomatous diseases, such as sarcoid (55) These patients more commonly

present with hyperprolactinemia and diabetes insipidus, due to the presence ofgranulomas in the pituitary stalk and hypothalamus An autoimmune processtermed lymphocytic hypophysitis has been associated with acquired hypo-

gonadotropic hypogonadism (56) Infectious agents, such as histoplasmosis,

tuberculosis, and rarely, coccidiomycosis or cryptosporosis, can infiltrate the

pituitary, often affecting the production of multiple pituitary hormones (55).

Additionally, hematopoietic tumors, such as leukemias and lymphomas, have

occasionally been reported to involve the pituitary to cause hypofunction (57) Finally, tumors may metastasize to the pituitary (57) These often invade via the

posterior pituitary and present with posterior as well as anterior pituitary function Tumors with a predilection for the pituitary include: prostate, lung,breast, melanoma, and renal cell cancer

dys-Table 5 Causes of Hypergonadotropic Hypogonadism

Klinefelter’s syndromeIntrauterine/testicular hypofunctionGenetic defects in gonadotropin actionMechanical disorders of the testesInfiltrative diseases of the testesGlycoprotein-secreting pituitary tumors

Hypergonadotropic Hypogonadism: High LH and/or FSH and Low Testosterone (Table 5)

K LINEFELTER ’ S S YNDROME

Klinefelter’s syndrome is a chromosomal disorder (XYY) of nondysjunction

that is associated with ultimate hypogonadism (58,59) There is lack of spermatic

development and tubules, resulting in small testes at any stage of pubertal opment Initially, the Leydig cells function to produce low levels of gonadalsteroids; however, with time, there is progressive tubular fibrosis and decline inandrogen production Men with Klinefelter’s present with delayed or haltingpuberty, eunochoid body habitus, gynecomastia, and small testes They areinfertile and, ultimately, need androgen replacement Patients with a mosaic karyo-type, XXY/XY, have less of the clinical hallmarks, do not have associated gyneco-

devel-mastia, and have less severe and a later onset of their hypogonadism (58,59).

I NTRAUTERINE /T ESTICULAR H YPOFUNCTION

There are several disorders that occur across gestation that result in absent orabnormal testicular function by birth (59,60) Testicular agenesis is associatedwith absent testes Vanishing testes syndrome is seen with testicular remnants thatdisappear soon after birth Finally, infants with cryptochidism are thought to havehad a late insult to the system With orchiopexy, the reproductive axis in theseboys can function normally; although studies have suggested that they have sub-tle deficiencies in spermatogenesis With aging, Leydig cell function declines,

and patients often require androgen replacement The underlying insult can betimed by the severity of the defect with the understanding that testicular develop-ment occurs prior to ovarian development at 9–11 wk of gestation.

G ENETIC D EFECTS IN G ONADOTROPIN A CTION

Mutations in the gonadotropin subunit receptor genes have recently beenidentified that result in abnormal pubertal development Some mutations of the

LH receptor are constitutively active, resulting in gonadotropin-independent

precocious puberty or testitoxicosis in boys (61) Inactivating mutations in the

LH receptor result in Leydig-cell hypoplasia and under-masculinization in males

(62–64) Inactivating FSH receptor mutations are associated with primary gonadal

failure in males and hypergonadotropic hypogonadism in females (65).

M ECHANICAL D ISORDERS OF THE T ESTES

Torsion of the testes can occur at any age Normal sexual function can beachieved with only one gonad, so that hypogonadism only occurs when the vas-cular supply is compromised to both gonads or the remaining gonad is impaireddue to another underlying problem

I NFILTRATIVE D ISORDERS OF THE T ESTES

Similar to the pituitary, the testes is the locus for a wide variety of disorders

(reviewed in ref 60) Iron deposition occurs in the testes of patients with

hemachromatosis, but the patients usually present with the pituitary rather thanthe primary testicular defect Mumps occurring after puberty is associated withrisk for subsequent hypogonadism Additionally, infections, such as tuberculo-sis, human immunodeficiency virus (HIV), histoplasmosis, and others, havebeen reported to infiltrate the male gonad Leukemia and lymphoma infiltration

is often seen, but is of unclear clinical relevance

G LYCOPROTEIN -S ECRETING P ITUITARY T UMORS

Although most patients with elevated gonadotropin and low testosteronelevels have a testicular locus of their hypogonadism, some patients with apituitary disorder present with similar laboratory abnormalities These arepatients with glycoprotein-secreting pituitary tumors, which produce somecomponent of the glycoprotein hormones: α-subunit, LH-β-subunit or FSH-β-subunit or rarely thyroid-stimulating hormone (TSH)-β-subunit (66–68) These

tumors, previously called nonfunctional tumors, occur in 30–35% of pituitarytumors They occur most commonly in older men and present with erectiledysfunction, hypogonadism, and mass effects causing headache or visual dis-

turbance (66–68) Based on the secretory pattern of the glycoprotein tumor, the

patient may have elevated FSH with or without elevated LH or α-subunit levelsand low, normal, or high testosterone levels Unfortunately, this is the same

pattern of hormonal abnormalities seen in men with early or late testicularfailure Attempts to use other markers, such as elevated prolactin levels, as asignal of stalk compression or gonadotropin response to thyrotropin-releasinghormone (TRH) have been disappointing in discriminating patients with pitu-

itary tumors (66–68) Magnetic resonance imaging (MRI) is the test of choice

to exclude a tumor in a patient with hypergonadotropic hypogonadism andsymptoms of a mass effect The tumors are often large at the time of clinicaldetection and are treated with transphenoidal surgical resection with occa-sional need for postoperative radiation After surgery, androgen and otherpituitary hormone replacement is often required depending on the status of theresidual normal pituitary

Table 6 Disorders that Present with Variable Patterns of Hypogonadism

AgingDiabetesAlcoholLiver disease

Disorders that Present with Variable Patterns

of Hypogonadism (Table 6)

D IABETES

Patients with diabetes often present with a combination of erectile dysfunction

with or without hypogonadism (69) Early in the disease process, the lack of

metabolic control is associated with a mixed erectile disorder, which is reversedwith improved blood glucose control Later in the disease process, the patientpresents with multifactorial erectile dysfunction and hypogonadism, which can

be hypogonadotropic or hypergonadotropic, and require androgen replacement

A GING

Many studies now show a gradual decline in androgen production from the

testes with age (70,71) Studies conflict on the timing of the process and the exact

number of men that are affected, in contrast to the uniform pattern of ovarian

failure seen at menopause in women (70,71) Both hypogonadotropic and

hypergonadotropic patterns have been reported Earlier data was flawed by theinclusion of sick hospitalized men with other disorders that underlie their hypo-gonadism Since co-morbid conditions increase with aging, however, the evalu-ation of all men for androgen deficiency is warranted

A LCOHOL AND L IVER D ISEASE

Excess alcohol has widespread effects on the reproductive axis It has direct

toxic effects on the Leydig cells, decreasing testosterone production (72–74).

Additionally, the associated central effects inhibit gonadotropin production

(72) Thus, a pattern of high or low gonadotropins with low testosterone can be

observed

TREATMENT ISSUES

Gonadotropin Replacement

In patients with a hypothalamic or pituitary defect, restoration of fertility as

well as androgen replacement, are options (75–77) Induction or reinduction of

spermatogenesis can be performed using pulsatile GnRH administration or acombination of human menopausal gonadotropins (HMGs) and human chori-onic gonadotropins (hCGs) Studies have shown that both are effective, butrequire parenteral administration and are costly Successful spermatogenesis

is predicted by the size of the testes upon initiation of therapy (75–77),

reflect-ing the severity of the gonadotropin deficiency When fertility is not desired,androgen replacement options are similar to those with a primary testiculardefect (see below)

Androgen Replacement

Androgen replacement should be considered for hypogonadism not only forrestoration of sexual function, but for effects on muscle mass, respiratory drive,

maintenance of bone mass, and cardioprotection (78) Testosterone

histori-cally was available by intramuscular (IM) injection of depotestosterone 200–

300 mg IM every (q) 2 to 3 wk Trough levels just below the normal range,obtained before the 4th dose, help to maintain an optimal level of replacement.Yearly prostatic exams, lipid profiles, and complete blood counts (CBCs) arerecommended to avoid side effects of worsening of benign prostatic hypertro-phy, increase in low density lipoprotein (LDL) cholesterol levels, or poly-cythemia Testosterone therapy is contraindicated in patients with underlyingprostatic cancer The availability of testosterone patches, and, more recently,gel formulations has revolutionized androgen replacement These productsallow a more steady-state replacement strategy without the highs and lows ofintramuscular administration Side effects of contact dermatitis and lack ofability to fine tune the dosing regimen with currently available androgenpatches remain problems that should be overcome with future improvements

in the drug delivery systems

Erectile Dysfunction

The currently available treatment options for erectile dysfunction include chanical devices and local or systemic drugs to modulate penile blood flow.Vacuum devices use suction to induce an erection and constriction rings to main-

me-tain the erection Although cumbersome, they are safe and effective (79,80).

Intracavernosal injections of alprostadil are useful in diabetic patients who arecomfortable with injections and often have a peripheral neuropathy that diminishes

the major side effect of pain after the injection (81) Other side effects include risk

of bleeding, infection, and priapism, all which occur only rarely Compliance withlong-term use has been poor with recent studies, suggesting that only 32% of

patients continued on the therapy (82) The intraurethral formulation of alprostadil (MUSE) has not been as successful as initial reports suggested (83,84).

The major advancements in the treatment of erectile dysfunction are the oraltherapies Yohimbine hydrochloride is an α-adrenergic antagonist and has beenshown to be effective only in psychogenic impotence The drug was noted to be20% more effective than placebo when given at 5.4 mg 3×/d (85) In these

patients, combination with trazadone, a serotonin agonist, may increase

effec-tiveness (85) The recent availability of sildenafil (Viagra) has popularized the

problem of erectile dysfunction Sildenafil works by inhibiting Type 5

phos-phodiesterase, which breaks down cGMP, the downstream target of NO (86,87).

Studies have shown the higher effectiveness in those with psychogenic tence, spinal cord injury, and those men with partial rather than complete erectile

impo-dysfunction (86,87) Patients with diabetes or after urological surgery have less

response to the drug Side effects include headache, dyspepsia, blue tion of vision, and postural hypotension Thus, the drug is contraindicated inpatients on nitrates Additionally, the drug half-life can be potentiated by othermedications, with aging, or with renal or hepatic disease Longer clinical expe-rience has suggested that for men with stable coronary artery disease, sildenafilhad no deleterious effects on clinical symptoms, exercise capacity, or exercise-

discolora-induced ischemia assessed by echocardiograpy (88) New agents for erectile

dysfunction include oral apomorphine (Ixense, Uprima), an opioid antagonist for

psychogenic impotence (89), and phentolamine, which is used to block the pinephrine-mediated smooth muscle relaxation and vasodilation (90).

nore-SUMMARY

Thus, after a careful history, physical exam, and selected laboratory tests, onecan classify patients with erectile dysfunction and/or hypogonadism into specific

categories that allow appropriate therapeutic interventions (91) Research is

underway to use the new advances in the understanding of the physiology of

erection and in disorders of the hypothalamic pituitary gonadal axis to targetmore specifically the treatment choices.

REFERENCES

1 Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E (1978) Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone Sci- ence 1978;202:631–633.

2 Marshall JC, Kelch RP Gonadotropin-releasing hormone: role of pulsatile secretion in the regulation of reproduction N Engl J Med 1986;315:1459–1468.

3 Crowley WF Jr, Whitcomb RW, Jameson JL, Weiss J, Finkelstein JS, O’Dea LS crine control of human reproduction in the male [review] Rec Prog Horm Res 1991;47:27–62.

Neuroendo-4 Hayes FJ, Hall JE, Boepple PA, Crowley WF Jr Clinical review 96: differential control of gonadotropin secretion in the human: endocrine role of inhibin J Clin Endocrinol Metab 1998;83:1835–1841.

5 Couse JF, Korach KS Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999;20:358–417.

6 Smith EP, Boyd J, Frank GR, et al Estrogen resistance caused by a mutation in the receptor gene in a man N Engl J Med 1994;331:1056–1061.

estrogen-7 Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley WF Jr Sex steroid control of pin secretion in the human male II Effects of estradiol administration in normal and gonadot- ropin-releasing hormone-deficient men J Clin Endocrinol Metab 71991;3:621–628.

gonadotro-8 Finkelstein JS, Whitcomb RW, O’Dea LS, Longcope C, Schoenfeld DA, Crowley WF Jr Sex steroid control of gonadotropin secretion in the human male I Effects of testosterone admin- istration in normal and gonadotropin-releasing hormone-deficient men J Clin Endocrinol Metab 1991;73:609–620.

9 Bagatell CJ, Dahl KD, Bremner WJ The direct pituitary effect of testosterone to inhibit gonadotropin secretion in men is partially mediated by aromatization to estradiol J Andrology 1994;15:15–21.

10 Mather JP, Moore A, Li RH Activins, inhibins, and follistatins: further thoughts on a growing family of regulators Proc Soc Exp Biol Med 1997;215:209–222.

11 Krane RJ, Goldstein I, Saenz de Tejada I Medical progress: impotence N Engl J Med 1989;321:1648–1659.

12 Korenman SG New insights into erectile dysfunction: a practical approach Am J Med 1998;105:135–144.

13 Ignarro LJ Nitric oxide as the physiological mediator of penile erection J NIH Res 1992;4:59–62.

14 Rajfer J, Aronson WJ, Bush PA, et al Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission N Engl J Med 1992;326:90–94.

15 Burnett AL, Lowenstein CJ, Bredt DS, et al Nitric oxide: a physiologic mediator of penile erection Science 1992;257:401–403.

16 NIH Consensus Conference Impotence JAMA 1993;270:83–90.

17 Feldman HA, Goldstein I, Hatzichristal DG, et al Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study J Urol 1994;151:54–61.

18 Saenz de Tejada I, Goldstein I, Azadzoi K, et al Impaired neurogenic and mediated relaxation of penile smooth muscle from diabetic men with impotence N Engl J Med 1989;320:1025–1030.

endothelium-19 Wierman ME Advances in the diagnosis and management of impotence Adv Intern Med 1999;44:1–17.

20 Korenman SG, Morley JE, Mooradian AD, et al Secondary hypogonadism in older men: its relation to impotence J Clin Endocrinol Metab 1990;71:963–969.

21 Mahoney J, Bruder JM, Balanoff A, et al Effectiveness of laboratory assessment of the pituitary-gonadal axis in patients with impotence [abstract 0038] Clin Res 1994;42:250.

22 Buvat J, Lemaire A Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy J Urol 1997;158:1764–1767.

23 Waldstreicher J, Seminara SB, Jameson JL, et al The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human J Clin Endocrinol Metab 1996;81:4388–4395.

24 Kallmann F, Schoenfeld WA, Barrera SE The genetic aspects of primary eunuchoidism Am

(LHRH)-27 Franco B, Guioli S, Pragliola A, et al A gene deleted in Kallmann’s syndrome shares ogy with neural cell adhesion and axonal path-finding molecules Nature 1991;353:529–536.

homol-28 Legouis R, Hardelin J-P, Levilliers J, et al The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules Cell 1991;67:423–435.

29 Rugarli EI, Ballabio A Kallmann syndrome: from genetics to neurobiology JAMA 1993;270:2713–2716.

30 Bray GA, Dahms WT, Swerdloff RS, Fiser RH, Atkinson RL, Carrel RE The Prader-Willi Syndrome: a study of 40 patients and a review of the literature Medicine 1983;62:59–80.

31 Vermeulen A, Kaufman JM, Deslypere JP, Thomas G Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men J Clin Endocrinol Metab 1993;76:1140–1146.

32 Santamaria JD, Prior JC, Fleetham JA Reversible reproductive dysfunction in men with obstructive sleep apnoea Clin Endocrinol 1988;28:461–470.

33 Kruse K, Sippell WG, Schnakenburg KV Hypogonadism in congenital adrenal hypoplasia: evidence for a hypothalamic origin J Clin Endocrinol Metab 1984;58:12–17.

34 Muscatelli F, Strom TM, Walker AP, et al Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism Nature 1994;372:672–676.

35 Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL The nuclear receptor steroidogenic factor

1 is essential for the formation of the ventromedial hypothalamic nucleus Mol Endocrinol 1995;9:478–486.

36 Samaan NA, Bakdash MM, Caderao JB, Cangir A, Jesse RH Jr, Ballantyne AJ ism after external irradiation Ann Intern Med 1975;83:771–777.

Hypopituitar-37 Constine LS, Woolf PD, Cann D, et al Hypothalamic-pituitary dysfunction after radiation for brain tumors N Engl J Med 1993;328:87–94.

38 Woolf PD, Hamill RW, McDonald JV, Lee LA, Kelly M Transient hypogonadotropic hypogonadism caused by critical illness J Clin Endocrinol Metab 1985;60:444–450.

39 Spratt DI, Bigos ST, Beitins I, Cox P, Longcope C, Orav J Both hyper- and hypogonadotropic hypogonadism occur transiently in acute illness: bio- and immunoactive gonadotropins J Clin Endocrinol Metab 1992;75:1562–1570.

40 Nachtigall LB, Boepple PA, Pralong FP, Crowley WF Jr Adult-onset idiopathic tropic hypogonadism—a treatable form of male infertility N Engl J Med 1997;336:410–415.

hypogonado-41 Sklar CA Craniopharyngioma: endocrine abnormalities at presentation Pediatr Neurosurg 1994;1:18–20.

42 Raisanen JM, Davis RL Congenital brain tumors Pathology 1993;2:103–116.

43 de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor N Engl J Med 1997;337:1597–1602.

44 Weiss J, Axelrod L, Whitcomb RW, Harris PE, Crowley WF, Jameson JL Hypogonadism caused by a single amino acid substitution in the β subunit of Luteinizing hormone N Engl

J Med 1992;326:179–183.

45 Matthews CH, Borgato S, Beck-Peccoz P, et al Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone Nat Genet 1993;5:83–86.

46 Layman LC, Lee E-J, Peak DB, et al Delayed puberty and hypogonadism caused by mutations

in the follicle-stimulating hormone beta-subunit gene N Engl J Med 1997;337:607–611.

47 Carter JN, Tyson JE, Tolis G, et al Prolactin-secreting tumors and hypogonadism in 22 men.

N Engl J Med 1978;299:847–852.

48 Bouchard P, Lagoguey M, Brailly S, Schaison G Gonadotropin-releasing hormone pulsatile administration restores luteinizing hormone pulsatility and normal testosterone levels in males with hyperprolactinemia J Clin Endocrinol Metab 1985;60:258–262.

49 Luton J, Thieblot P, Valcke J, Mahoudeau JA, Bricaire H Reversible gonadotropin deficiency

in male Cushing’s disease J Clin Endocrinol Metab 1977;45:488–495.

50 MacAdams MR, White RH, Chipps BE Reduction of serum testosterone levels during chronic glucocorticoid therapy Ann Int Med 1986;104:648–651.

51 Molitch ME Clinical manifestations of acromegaly Endocrinol Metab Clin North Am 1992;21:597–614.

52 Kelly TM, Edwards CQ, Meikle AW, Kushner JP Hypogonadism in hemochromatosis: reversal with iron depletion Ann Int Med 1984;101:629–632.

53 Tavill AS Clinical implications of the hemochromatosis gene N Engl J Med 1999;341:755–756.

54 Cundy T, Butler J, Bomford A, Williams R Reversibility of hypogonadotropic hypogonadism associated with genetic haemochromatosis Clin Endocrinol 1993;38:617–620.

55 Bell NH Endocrine complications of sarcoidosis Endocrinol Metab Clin North Am 1991;20:645–654.

56 Cosman F, Post KD, Holub DA, Wardlaw SL Lymphocytic hypophysitis: report of 3 new cases and review of the literature Medicine 1989;68:240–256.

57 McDermott MT Infiltrative diseases of the pituitary gland In Wierman ME, ed Diseases of the Pituitary: Diagnosis and Treatment Humana, Totowa, NJ, 1997; pp 305–322.

58 Smyth CM, Bremner WJ Klinefelter syndrome Arch Intern Med 1998;158:1309–1314.

59 Diemer T, Desjardins C Developmental and genetic disorders in spermatogenesis Hum Reprod 1999;Update 5:120–140.

60 Griffin JE, Wilson JD Disorders of the testes and the male reproductive tract In Wilson JD, Foster

DW, eds Williams Textbook of Endocrinology W.B Saunders, Philadelphia, 1992, pp 799–852.

61 Kremer H, Martens JW, van Reen M, et al A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precociouis puberty J Clin Endocrinol Metab 1999;84:1136–1140.

62 Laue L, Wu SM, Kudo M, et al A nonsense mutation of the human luteinizing hormone receptor gene in Leydig cell hypoplasia Hum Mol Genet 1995;4:1429–1433.

63 Kremer H, Kraaij R, Toledo SP, et al Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene Nat Genet 1995;9:160–164.

64 Latronico AC, Anasti J, Arnhold IJP, et al Testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene N Engl

J Med.1996;334:507–512.

65 Aittomaki K, Lucena JL, Pakarinen P, et al Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure Cell 1995;82:959–968.

66 Snyder PJ Gonadotroph cell adenomas of the pituitary Endocr Rev 1985;6:552–563.

67 Jameson JL, Klibanski A, Black PM, et al Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas J Clin Invest 1987;80:1472–1478.

68 Snyder PJ, Bigdeli H, Gardner DF, et al Gonadal function in fifty men with untreated pituitary adenomas J Clin Endocrinol Metab 1979;48:309–314.

69 Dunsmuir WD, Holmes SA The aetiology and management of erectile, ejaculatory, and fertility problems in men with diabetes mellitus Diabet Med 1996;13:700–708.

70 Neaves WB, Johnson L, Porter JC, Parker CR, Petty CS Leydig cell numbers, daily sperm production and serum gonadotropin levels in aging men J Clin Endocrinol Metab 1984;59:756–763.

71 Swerdloff RS, Hever D Effects of aging on male reproductive function In Korenman SG, ed Endocrine Aspects of Aging Elsevier Biomedical, New York, 1982, pp 119–135.

72 Korenman SG, Morley JE, Mooradian AD, et al Secondary hypogonadism in older men: its relation to impotence J Clin Endocrinol Metab 1990;71:963–969.

73 Van Thiel DH, Cobb CF, Herman GB, Perez I, Gavaler JS An examination of various nisms for ethanol-induced testicular injury: studies utilizing the isolated perfused rat testes Endocrinology 1981;109:2009–2015.

mecha-74 Iranmanesh A, Velhuis JD, Samojlik E, Rogol AD, Johnson ML, Lizarralde G Alterations in the pulsatile properties of gonadotropin secretion in alcoholic men J Androl 1988;9:207–214.

75 Burris AS, Rodbard HW, Winters SJ, Sherins RJ Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted

by initial testicular size J Clin Endocrinol Metab 1988;66:1144–1151.

76 Whitcomb RW, Crowley WF Diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men J Clin Endocrinol Metab 1990;70:3–7.

77 Schopohl J, Mehltretter G, von Zumbusch R, et al Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idiopathic hypothalamic hypogo- nadism Fertil Steril 1991;56:1143–1145.

78 Bagatell CJ, Bremner WJ Androgens in men—uses and abuses N Engl J Med 1996;334:707–714.

79 Baltaci S, Aydos K, Kosa A, et al Treating erectile dysfunction with a vacuum tumescence device: a retrospective analysis of acceptance and satisfaction Br J Urol 1995;76:757–760.

80 Vrijhof HJ, Delaere KP Vacuum constriction devices in erectile dysfunction: acceptance and effectiveness in patients with impotence of organic or mixed aetiology Br J Urol 1994;74:102–105.

81 Linet OI, Ogring FG Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction N Eng J Med 1996;334:873–877.

82 Sundaram CP, Thomas W, Pryor LE, et al Long-term follow-up of patients receiving injection therapy for erectile dysfunction Urology 1997;49:932–935.

83 Padma-Nathan N, Hellstrom WJ, Kaiser FE, et al Treatment of men with erectile dysfunction with transurethral alprostadil Medicated Urethral System for Erection (MUSE) Study Group.

89 Altwein JE, Keuler FU Oral treatment of erectile dysfunction with apomorphine SL Urology International 2001;67:257–263.

90 Wagner, G., Lacy, S., Lewis, R., et al (1994) Buccal phentolamine: a pilot trial for male erectile dysfunction at three separate clinics Int J Impot Res 6:D78–D80.

91 Wierman ME, Cassel CK Erectile dysfunction: a multifaceted disorder Hosp Pract 1998;33:65–90.

From: Contemporary Endocrinology: Handbook of Diagnostic Endocrinology

Edited by: J E Hall and L K Nieman © Humana Press Inc., Totowa, NJ

THE PHYSIOLOGY OF NORMAL MENSTRUAL FUNCTION

MENSTRUAL DYSFUNCTION IN REPRODUCTIVE AGED WOMEN

ABNORMAL BLEEDING IN CHILDHOOD

ABNORMAL BLEEDING IN POSTMENOPAUSAL WOMEN

CONCLUSION

REFERENCES

THE PHYSIOLOGY OF NORMAL MENSTRUAL FUNCTION

A pattern of regular ovulatory menstrual cycles is achieved through theexquisite functional and temporal integration of hormonal secretion from thehypothalamus, the pituitary, and the ovary This classic endocrine cascade isinitiated by pulsatile secretion of gonadotropin-releasing hormone (GnRH)from the hypothalamus into the pituitary portal venous system The subsequentrelease of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)from the anterior pituitary stimulates ovarian follicular development, ovula-tion, and corpus luteum formation The uterus in turn responds to ovariansteroids by endometrial proliferation, vascularization, and glandular develop-ment In the absence of implantation, ovarian hormonal support wanes, andendometrial shedding ensues This pattern of events is accompanied by dra-matic changes in LH, FSH, estradiol, progesterone, inhibin A, and inhibin B

across normal menstrual cycles (1) (Fig 1) In addition, the pulsatile

stimula-tion of pituitary hormone secrestimula-tion by GnRH results in pulsatile secrestimula-tion of

LH and to a lesser extent FSH, which also varies across the cycle, reflecting

changes in the frequency of the GnRH pulse generator (2) (Fig 2).

The median menstrual cycle length of the American woman is 28 d, with arange between 25–35 d considered normal The 7-yr intervals immediately fol-lowing menarche and preceding menopause are marked by the greatest amount