HYPOGONADISM

DEPT OF ENDOCRINOLOGYCHIEF:DR.SANGUMANI MD ASST PROF:DR.SRIDHAR MD DM DR.SOMASUNDHARAM MD

NORMAL PUBERTAL DEVELOPEMENT

ANDROGEN METABOLISM AND ACTIONS

LH SECRETORY PATTERN

IN A PT WITH HYPOGONADOTROPIC HYPOGONADISM

FETAL ANDROGEN DEFECIENCY

AMBIGOUS GENITALIA

Microphallus

Pseudovaginal

Perineoscrotal Hypospadias

Bifid Scrotum

Cryptorchidism

PRE PUBERTAL ANDROGEN DEFICIENCY-SYMPTOMS

DELAYED PUBERTY

• Loss Of Libido• Reduced Nighttime Or

Morning Spontaneous Erections

• Reduced Motivation And Initiative

• Dimi. Strength And Physical Performance

• Breast Enlargement And Tenderness

• No Spermarche/Infertility

SIGNS OF ANDROGEN INSUFFIENCY

eunuchoidism,

Infantile genitalia

Small testis

Loss of male hair pattern

DispoportionatelyLong arms and legs relative

to heightAdults-low bone mineral

density

PSYCHOLOGICAL SYMPTOMS

PSYCHOLOGICAL

Poor concentration and memory

Fine facial skin wrinkling(lateral

to orbit and mouth)

Increased sleepiness

Feeling sad or blue

/irritability

HYPOGONADISM

PRIMARY

•Androgen Def. With Impaired Sperm Production•Isolated Impairment In Sperm Production

SECONDARY

•Androgen Def. With Impaired Sperm Production•Isolated Impairment In Sperm Production

PRIMARY AND SECONDARY SUB CLASSIFICATIONS

COMBINED ANDROGEN AND SPERM

Congenital Acquired Systemic

ISOLATED IMPAIREMENT IN SPERM PRODUCTION

Congenital Acquired Systemic

PRIMARY HYPOGONADISM –COMBINED DEFECIENCY OF ANDROGEN AND SPERM PRODUCTION

CONGENITAL• Klinefelter• Myotonic dystrophy• Noonan• B/L Cong. Anorchia• Down Syndrome• LH Receptor Mutations• Poly glandular

Autoimmune Syndrome

ACQUIRED• B/L Surgical

Castration• Drugs• Radiation

SYSTEMIC• CKD• CLD• Aging• Malignancy• Sickle Cell• Spinal Cord Injury• Infiltrative

Disorders

PRIMARY HYPOGONADISM-ISOLATED IMPAIREMENT OF SPERM PRODUCTION

CONGENITAL• Cryptorchidism• Varicocele• Down• Myotonic Dystrophy• Sertoli Cell Only

Syndrome• Primary Ciliary

Dyskinesia

ACQUIRED• Orchitis• Radiation• Drugs

SYSTEMIC• Acute Febrile Illness• Malignancy• Idiopathic

Azoospermia • Spinal Cord Injury

SECONDARY HYPOGONADISM –COMBINED ANDROGEN DEFICIENCY AND SPERM PRODUCTION

CONGENITAL

Constitutional

Hemochromatosis

IHH

ACQUIRED

Hyperprolactinemia

Drugs

Hypopituitarism

Lymphocytic.

SYSTE

MIC

Glucocorticoid Excess

Chronic Organ Failure

Chr. Systemic Illness

SECONDARY HYPOGONADISM-ISOLATED IMPAIREMENT OF SPERM PRODUCTION

CONGENITA

L

CONGENITAL ADRENAL HYPERPLASIA

Isolated FSH Deficiency

FSH-ß Mutations

ACQUIREDTestosterone And Anabolic SteroidsMalignancyHyper prolactinemiaAndrogen Secreting Tumors

KLINEFELTER’S SYNDROME47xxy(ma

ternal non

dysjunction)

Small firm testis,eunuchoidism,azoospermia,inc

Gnrs

Taurodontism,increased lower segment

Cag repeats

Systemic disorders

HORMONAL PROFILE IN A PATIENT WITH KLINEFELTER

CONGENITAL DISORDERS CNTD….

CRYPTORCHIDISM B/L CONGENITAL ANORCHIA(Vanishing testes syn./testicular regression sequence)

Premature/LBW/SGA

Testicular dysgenesis

Azoospermia-50%,oligo-75%

Ectopic/retractile testis

Phenotypically and genotypically male

B-hcg stimulation testing

Amh

CNTD….

Apeced-1(primary hypogonadism)

Type 2-circulating steroid cell antibodies

DOWN SYNDROMEPrimary

Hypogonadism With Selective Elevation

Of Fsh

CAH

CAHTesticular Adrenal Rest

TumoursIncreased Androgen-sec

HypogonadismTreatment With Steroids Reduces Tumour Size But Semniferous Atrophy And

Leydig Loss

EXTERNAL INFLUENCES

LH RECEPTOR MUTATIONS• Micropenis• Hypospadias• Undervirilization

DRUGS AND RADIATION• Ketoconazole>400 Mg/D• Spironolactone• Active Cell Replication• Radiation 600-800 Cgy

INFECTIONS• Mumps-10days after parotitis,orchitis

even. clinically u/l degenerative changes occur b/l

• HIV per se –sec hypogonadism• primary in HIV

oppurtunistic(cmv,mac,toxoplasmosis)

SYSTEMIC DISEASESincreased SHBG,dec free testosterone

Alcohol increases estrogen synthesis

Prolactin-supresses FSH,LH

Spironolactone(ascites)-supresses androgen

CHRONIC LIVER

DISEASE

CNTD…Combined Primary And Secondary

Increased FSH,LH due to reduced clearance

HD/PD does not restore testosterone levels

Transplantation restores testosterone.

CHRONIC KIDNEY DISEASE

SECONDARY HYPOGONADISMCONSTITUTIONAL DELAY IN

GROWTH AND PUBERTY

CDGP-transient secondary hypogonadism cause of delayed puberty in 65%.

Delayed puberty suspected if sexual maturation and testis size less than 4ml

at 14yrs os age.

Increased prevalence in families with IHH.so considered a variant of IHH

Height age and bone age less than chronological age.

Eventually boys with CDGP undergo normal growth and sexual

development

Normal height is attained but midparental height may not be

acheieved.

GROWTH PATTERNS

HEMOCHROMATOSIS

Hemochromatosis presents

with combined secondary

hypogonadism

Occurs when serum ferritin levels exceed

1500 micro/dl.

With hepatic cirrhosis ,SHBG levels increases reducing levels

of free testosterone.

Hypogonadism reverses with therapeutic phlebotomy early in trhe

course of iron overload

IHH

KALLMAN AND VARIANTST

1-KAL1

Failure Of Gnrh Neuronal MigrationSynkinesiaU/L Renal Agenesis

T2-FGFR

Normosmic IHHDental AbnormalitiesCleftlipSyndactylyBrachydactyly

T3/

4-PROK,PROKR

severe kallmans to normosmic IHH

ACQUIRED DISORDERS

•Prolactin Secreting Adenoma(>250ng/Dl)•Pituitary Stalk Deisease(stalk Compression From Non Prolactin Adenoma,traumatic)-dopamine Mediated(20-250 Ng/Dl)

HYPERPROLACTINEMIA

•Antipsychotics/prokinetics/antihypertensives•<100ng/dl

DRUGS•Mild hyperprolactinemia does not cause clinically significant hypogonadism•Long standing and severe-enlarged pituitary

HYPOTHYROIDISM

SYSTEMIC DISEASES

CUSHING SYNDROMEHypothalamic Inhibition Of Gnrh,direct Effect On

TestisDoses As Low As 7.5

Mg/Dl Can Cause Hypogonadism.

CHRONIC LIVER DISEASE

Regardless Of Etiology-primary In Mild To

ModerateSecondary In Severe

COPDHypoxia

MalnutritionSteroids

CNTD…nutritional/anorexia-3-5 days of starvation

supresses GnRH,testosteroneAdequate food intake and weight gain replaces LH

pulse

Chronic endurance exercise

Acute starvation supresses leptin.HUMAN r LEPTIN increase testosterone.

Moderate obesity-secondary hypogonadism

SHBG CONCENTRATIONS

MODERATE OBESITYT2-DM

NEPHROTIC SYNDROMECORTICOIDS

ADROGENS,PROGESTINSHYPOTHYROIDISM

ACROMEGALY

AGINGHEPATIC CIRRHOSIS

ESTROGENSHYPERTHYROIDISMANTICONVULSANTS

HIV

HORMONAL PROFILE

GOALS OF THERAPY

RESTORE LIBIDO AND ERCETILE

FUNCTION

INCRASE MUSCLE MASS AND

STRENGTH AND IMPROVING

PHYSICAL FUNCTION AND PERFORMANCE

INCREASE BMD

HEMATOCRIT

MALE HAIR GROWTH

PRINCIPLES OF THERAPY

TO TREAT AN

DROGEN DEFECIENCY

•PARENTERAL(Tes. Enanthate/Cypionate/Undecanoate)•TRANSDERMAL(Non Scrotal Patch/1% Gel)•TRANSBUCCAL

TO INITIATE AND MAINTAI

N SPER

M PRODUCTION

IN MEN WIT

H HYPO.

HYPOGONADISM

• Added Initially To Stimulate Testosterone And Sperm Production(HCG)•ADDED TO HCG TO STIMULATE SPERM Production(FSH,hMG,hFSH/rhFSH)•TO STIMULATE SPERM Production(GnRH)

SERUM TOTAL TESTOSTERONE CONC IN MEN TREATED WITH TES.ENANTHATE FOR 12 WEEKS

TOTAL SPERM COUNT RESPONSE TO GONADOTROPIN THERAPY

MONITORING DURING THERAPY

INCREASED Hcr(IF Hcr>54% REDUCE DOSAGE UNTIL Hcr REUCES TO

NORMAL AND REINITIATE AT LOWER DOSE)

PSA increase>1.4 ng/ml within 12mnth period

PSA velocity >0.4 ng/ml/yr after 6mnths of treatment with

TESTOSTERONENodule/induration on DRE

AUA/IPSS SCORE>19

OSAS

ERYTHROCYTOSIS HYPERTENSION CCF /WEIGHT GAIN

ACNE AND OILY SKIN GYNECOMASTIA

NEWER FORMULATIONS

TESTOSTERONE BUCICLATE SUBLINGUAL/BUCCAL TESTOSTERONE

SARM-ENOBOSARM,LIGANDROL(under

preclinical testing)