MALE GONADAL FUNCTIONS AND DYSFUNCTIONS

SAHEED OLUWASINA OSENI (DVM)

REPRODUCTIVE ENDOCRINOLOGY

(BSC 6936)

FLORIDA ATLANTIC UNIVERSITYDEPARTMENT OF BIOLOGICAL

SCIENCES

BY:

SAHEED OLUWASINA OSENI (DVM)

CLASS PRESENTATION

PRESENTATION OUTLINE

Quick Overview Male gonadal (Testicular) functions Male gonadal Dysfunction (Androgen

Deficiencies) Male Hypogonadism Secondary hypogonadism-Opiates , Kallman’s

syndrome and idiopathic hypogonadotropic hypogonadism

Primary hypogonadism-Klinefelter’s syndrome, Nooman’s syndrome and XX males

Questions and Answers References

Hypothalamic-Pituitary-Testicular Axis

1. Tubular compartment

Germ cells

Sertoli cell: also known as the nurse or mother cells or sustentacular cells support spermatogenesis. Their proliferation is triggered by testosterone and FSH secretion (has FSH-receptor on its membranes) and also Inhibited by inhibin.

Sperm cells

Two cellular compartments involved in spermatogenesis

2. Interstitial Compartment

Leydig cells:Produce testosterone (dihydrotestosterone, DHEA and androstenedione) by respond to luteinizing hormone (LH) with steroid production (primarily testosterone).

Functions of testosterone

Converted to DHT (more active)in tissues e.g. prostate gland.

Testosterone is also converted to oestradiol in adipose tissue by aromatase enzyme

Actions– Male sexual differentiation– Maintains male secondary sexual characteristics – Regulation of GnRH secretion– Spermatogenesis– Normal male sexual function and behaviour– Maintenance of bone mineral density

TESTOSTERONE TARGET ORGANS AND FUNCTION

DHT &Estradiol

***This will be a hard task for someone with hypogonadism due to fatigue and loss of strength***

I’VE GOT THE ‘T’ FOLKS

Androgen Deficiency Symptoms

Musculoskeletal – Decreased vigour and physical energy– Diminished muscle strength

Sexuality– Decreased interest in sex– Reduction in frequency of sexual activity– Poor erectile function/arousal– Loss of nocturnal erections– Reduced quality of orgasm– Reduced volume of ejaculate

Mood disorder and cognitive function– Irritability & lethargy– Decreased sense of well-being– Lack of motivation– Low mental energy– Difficulty with short-term memory– Depression– Low self-esteem– Insomnia– Nervousness

Androgen Deficiency Symptoms

Vasomotor and nervous– Hot flushes– Sweating

Androgen Deficiency Symptoms cont’d

– Diminished muscle mass

– Loss of body hair

– Abdominal obesity

– Gynecomastia

– Testes frequently normal, occasionally

small

Physical Signs

Androgen Deficiency Symptoms

History and Physical (Symptoms and Signs)

Exclude reversible illness, drugs,

nutritional deficiency

Do you suspect altered SHBG?

Low T

Morning Total T

Normal T, LH+FSH

Not HypogonadismFollow up

Normal T

Repeat TCheck LH+FSH

If altered SHBG,

Use free or bio- T

Semen analysis

if fertility issue

Keys: ‘T’ means Testosterone

How to investigate for Androgen Deficiencies

MALE HYPOGONADISM: Definition

A decrease in either of the two major functions of the testes: – sperm production – testosterone production

Types of Male Hypogonadism

Secondary hypogonadism

Primary hypogonadism

Confirmed low T (Total < 300 ng/dl)OR

Free or Bio T < normal (Free T <5 ng/dl)

Low TLow / normal LH+FSH

Prolactin, iron saltsOther pituitary hormones

Low THigh LH+FSH

KaryotypeKlinefelter SyndromeOther Testicular Insult

Secondary HypogonadismPrimary Hypogonadism

MRI in certain cases

How too know which type of hypogonadism you are dealing with

during tentative diagnosis

Secondary hypogonadism

Hypothalamic/pituitary cause (often presents as delayed puberty or infertility)

Genetic, structural or environmental causes

Possible aetiologies

Kallman’s syndrome

Failure of GnRH secretion and neuronal development Associated with anosmia (smelling disorder) and

hyposmia (75%) 1 in 10,000 Male : female ratio 4:1 Diagnosis

– Low/undetectable testosterone, LH and FSH– Other pituitary functions are normal– Normal hypothalamus/pituitary on MRI, but absence of

olfactory bulb Treatment

– Exogenous testosterone replacement– Gonadotrophins if fertility required

Idiopathic hypogonadotrophic

hypogonadism Acquired or genetic (rare cases of GnRH

receptor gene mutation) In acquired cases men may

– have gone through normal puberty– Present with low libido, erectile dysfunction

or infertility– Acquired cases may go into remission

after testosterone or gonadotropin therapy.

Miscellaneous causes of secondary hypogonadism

Stress Systemic illness Structural

– Any pituitary tumour esp. prolactinomas– Associated with other hormonal deficiencies

Drugs– Anabolic steroids– Cocaine and opiates– Any drugs causing hyperprolactinaemia

Hemochromatosis Endocrine – Cushing's, prolactinoma Prader-Willi syndrome – 15q mutation – obesity and

mental retardation Laurence-Monn-Biedl syndrome – obesity and mental

retardation.

Primary hypogonadism

Genetic– Klinefelter’s syndrome– XX males– Noonan’s syndrome (46XY)

Acquired– Trauma– Orchitis– Cryptorchism– Post chemotherapy/radiotherapy– Chronic illness– Drugs- opiates, alcohol, sulfasalazine, colchicine

Opiates and hypogonadism

Long-acting opioid analgesics suppress the hypothalamic-pituitary gonadal axis in men and produce symptomatic androgen deficiency (up to 74%).

Opiates of all kinds cause reduced release of GnRH, LH, testosterone (free testosterone).

This usual follows a dose dependent exposure and

correlates to reduction in libido and subjective erectile dysfunction.

Also leads to osteoporosis

NB: **I did not find any literature on special treatment or testosterone replacement in this group. (though I suspect using a opioid antagonist or stopping use of opiates might work)

Hypogonadism in men consuming sustained-action oral opioids. Daniell HW. J Pain. 2002 Oct;3(5):377-84.

Klinefelter’s syndrome

First described by Harry Klinefelter 1942 1:500 men affected Extra X chromosome causes primary hypogonadism

with testosterone deficiency Clinically

– Reduced testicular volume– Tall eunachoid stature– Reduced body hair– Gynaecomastia– Intellectual dysfunction in 40%

20 time increased risk of carcinoma of breast

Klinefelter’s Syndrome

Most common endocrine cause of Primary hypogonadism

FSH always T variably affected (T or normal) Fertility rare (in mosaics only) Treatment: T only if needed

– Will not reverse infertility

Signs: Eunuchoidal body

habitus Variable

androgenization Long extremities

(LS>US) Karyotype: XXY

Klinefelter’s Syndrome

NB: So the klinefactor is having 47 chromosomes instead of 46

Trisomy

Diagnosis

Low testosterone Elevated LH/FSH Azospermia Definitive diagnosis is

based on karyotyping– 47XXY or 46XY/47XXY

(mosaic)

Management

Counselling– Klinefelter’s Syndrome

Association UK[http://www.ksa-

uk.co.uk]

Androgen replacement therapy

Noonan Syndrome

Autosomal dominant disorder (variable penetrance) Normal karyotype Phenotype is like that of Turners syndrome

– Low set ears– Right sided congenital heart defects (left-sided in

Turners)– Epicanthic folds– Short stature– Webbed neck– Cryptorchism (50% of males)– Primary hypogonadism

Can affect either sex

XX males

1 in 10,000 births These patients have a translocation of

part of the Y chromosome with the X chromosome

Phenotype is similar to Klinefelter's May also have short stature and

hypospadias

QUESTIONS &

ANSWERS

CASE STUDY TO DISCUSS IN CLASS

A 35 year old man presents with infertility & azoospermia. He was at puberty at the age of 15, has normal libido and shaves every other day.

He is 72” tall, 180#, with gynecomastia and small testes Has normal thyroid & phallus The Testosterone level is low, LH high, FSH high

QUESTION??? Can you guys give me your tentative diagnosis with

reasons and also the best diagnostic test to establish your definitive diagnosis?

o

Friends its time for us

to think as a clinician and endocrinolog

istk

oCase 1

CASE STUDY TO DISCUSS IN CLASS

A 19 year old boy presents with inability to smell his girl friends perfume & azoospermia

He is 175cm tall, 53kg weight, with his arm slightly than his height at 177.5cm. He had a normal voice and his pubic hair were adult like in texture and type.

On endoscopy his olfactory fissures were patent and MRI images shows that the olfactory bulb is absent.

The Testosterone level is low and other pituitary functions were found to be normal with MRI.

QUESTION??? Can you guys give me your tentative diagnosis with

reasons and what type of hypogonadism is this disease?

o

Friends its time for us

to think as a clinician and endocrinolog

istk

oCase 2

CASE STUDY TO DISCUSS IN CLASS

A 54 year old man was asked by his wife of 35years old to go visit a physician concerning his inability to perform well in bed (low libido and erectile dysfunction). The man in addition complaint to the clinician about a long time worsening fatigue.

On physical examination, he is found to be obese with BMI=31. There is no evidence of gynecomastia The testicles and prostate are normal Lab evaluation reveals serum testosterone level of 180ng/dl (ref. range: 249-836)

QUESTION??? What is your tentative diagnosis and why?

o

Friends its time for us to

think as a clinician and endocrinologi

stk

oCase 3

THANKS FOR LISTENING

Total vs. Free vs. BioavailableTestosterone (male)

60%

38%

2%

Affinity for SHBGis at least 4X higher vs. albumin

Greenspan’s Basic &Clinical Endocrinology, 8th edition

REFERENCES

Greenspan’s Basic &Clinical Endocrinology, 8th edition

Per Williams Textbook of Endocrinology 11th edition

[http://www.ksa-uk.co.uk] Wikipedia [www.wikipedia.org]: kallman’s,

klinefecter’s, Nooman’s syndrome, XX males, etc....