Biochemical Aspects
of Male & Female
Subfertility/ Infertility
Objectives of the Lecture
 Recall factors required for conception
 Recall the definition of infertility.
 Understand the correlation of biochemical and clinical aspects of the
common endocrinal causes infertility in males and females.
 Recognizing the biochemical aspects of overall laboratory
investigations of infertility in males and females.
Requirements for Conception
•
•
•
•
•
Production of healthy ova & sperm
Unblocked tubes that allow sperm to reach the ova
The sperms ability to penetrate & fertilize the ova
Implantation of the embryo into the uterus
Finally a healthy pregnancy
Infertility/ Subfertility
The inability to conceive
following unprotected sexual intercourse
for 1 year (age < 35)
or 6 months (age >35)
Infertility Etiology
Evaluation of the Infertile couple
•
•
•
•
History
Physical examination
Semen analysis (to exclude male causes)
Determination of ovulation
– Basal body temperature record
– Serum progesterone
– Ovarian reserve testing
• Endocrine investigations
• Hysterosalpingogram (for uterus & tubes)
LABORATORY
Diagnostic Approaches of
Male Infertility
Seminal Fluid Analysis
Hormonal Assay
Laboratory Seminal Fluid Analysis
Normal
Constituents of
Seminal Fluid
Seminal Vesicle Secretion
Fructose:
source of energy for sperms
Needed for sperms motility
Prostaglandins:
Controlling sperm movement
& sperm penetration of cervical mucus
Fibrinogen-like substance :
Cause of viscosity of semen (coagulation)
Prostatic Secretion
pH 6.5 (weak acidic)
Reduces acidity of vag.sec
Contains:
vesiculase
Reduces semen viscosity
Acid phosphatase
Spermine: bacteriostatic
Testicular
Secretion
Source of Secretion
Testis
% Ejaculate
5%
Seminal vesicles
40 – 80 %
Prostate
13 – 33 %
Bulbo-urethral & urethral
glands
2-5%
Laboratory Seminal Fluid Analysis
Physical Analysis



Volume
Liquefaction time (after coagulation)
pH
Microscopic Analysis





Sperm
Sperm
Sperm
Sperm
Sperm
count
morphology
motility
viability
agglutination
Biochemical Analysis


Fructose test
Acid phosphatase
Others
 Antisperm antibody
Main Causes of Male Infertility
Testicular Causes:






Radiation (as X-ray, etc)
Trauma of testis
Varicocele
Orchitis (inflammation of the testis)
Systemic disorder causing low testosterone or spermatogenesis
Abnormal sperm morphology
Secondary Hypogonadism: (Low GnHR, FSH , LH)


Hypothalamic causes
Pituitary causes
Hyperprolactinemia
Altered Sperm Transport:
 Obstruction of vas deference
 Congenital absence vas deferens
 Vasectomy (sperm count reaches zero after 3-6 months)
 Congenital absence or obstruction epidedimes
 Erectile dysfunction (ED)
 Retrograde ejaculation
Other less common causes
 As antiandrogens medications intake
Diagnostic Approach to Infertility in Males
Seminal Fluid Analysis
Normal Sperm Analysis
No endocrine tests are
required
Low Sperm Count
FSH & LH
 Testosterone
Primary
hypogonadism
(e.g. testicular)
Orchitis, Radiation, Trauma
Testosterone
 FSH & LH
Secondary
hypogonadism
Hypothalamic
or Pituitary
Disease
NORMAL
Hormonal
Profile
Testosterone
FSH & LH
Prolactin
Abnormal Profile
Testost.
 Prolactin
Vas
Deference
Obstruction
Hyperprolactinemia
Causes ??
Other Anomalies
Abnormal Forms
Sperm Agglutin.
Antobodies
Pus cells
RBCs
Vasectomy
Trauma
Congenital
Absence
Seminal
Vesicle
&
Ejacul. Duct
Prostate
Prostatic
Invest.
Acid
Phosphatase
PSA
Low Semen Amount
Low or no Semen Coagulation
Low Semen pH
Low Sperm Motility & Viability
Low Semen Fructose
Primary Hypogonadism
(Primary Testicular Failure)
•
Damage of BOTH the interstitial cells & semniferous tubules 
Testosterone
Gonadotrophins (LH & FSH)
•
Damage of Only semniferous tubules 
in FSH (but LH normal)
Testosterone normal (as interstitial cells intact)
Varicocele
A Cause of Male Infertility
Common, disease affecting 15% of men overall & 40% of men with known
infertility.
Varicocele is an abnormal enlargement of the pampinform plexus of veins in the scrotum.
Pampinform plexus of veins drains the testicles.
Varicocele may raise the temperature
the testicles or cause blood to back up in
the veins supplying the testicles.
Varicocele seem to help damage or kill the sperm.
The detrimental effect of varicocele on sperm production is progressive and due to
reduction in supply of oxygenated blood & nutrient material to the sperm
production sites, which persistently reduces the quality & the quantity of the
sperms, leading to reduction in their fertility capacity with time
Assessment of Sperm Morphology
Normally the sperm count contains fewer
than 20 % abnormal forms e.g. bitailed, short
tailed , 2 heads …..etc.
A Cause of Male Infertility
LABORATORY
Diagnostic Approaches of
Female Infertility
Hormonal Assay
Common Causes Female Infertility
Ovulation Disorders Causes:




Aging
Diminished ovarian reserve
Premature ovarian failure
Endocrine disorders (as PCOS)
Tubal Causes:




Pelvic inflammatory disease
Tubal Surgery
Previous ectopic pregnancy
Salpingectomy
Uterine/Cervical Causes:





Congenital uterine anomaly
Fibroids
Endometriosis
Poor cervical mucus quantity/quality
Infection
Diagnostic Approach to Infertility in Females
Detailed History & Physical Examination
Normal menses
Amenorrhea, Oligomenorrhoea
Investigations for Ovulation
Progesterone n day 21 (mid luteal)
<10 nmol/L
Ovulation
No Ovulation
Pituitary or
hypothalam.
High FSH
& LH
1ry
Ovarian Failure
+ ve
-ve
>30 nmol/L
Low FSH
& LH
Pregnancy Test
No
Further
Tests
LH, FSH & Prolactin
High LH
Low FSH
PCOS
High
Prolactin
Investigation for a cause of
hyperprolactinemia
All Normal
Further
Investig.
Endocrine causes of infertility in Females
Endocrine investigation is of diagnostic value for women who
have:
• Irregular or no menstruation
• No ovulation
Endocrine causes of infertility in women





Primary ovarian failure:  oestradiol & ↑ gonadotrophins (FSH & LH)
Hyperprolactinemia (↑ blood prolactin)
Polycystic ovary syndrome (PCOS)…
Cushing’s syndrome (↑ steroid hormones)
Hypogonadotrophic hypogonadism (↓ pituitary hormones FSH & LH): rare
Cushing Syndrome
• Overproduction of cortisol by the adrenal cortex mainly caused by adrenal
cortical adenoma
• Due to increased production of adrenal cortical androgens
(androstendione)
Hyperprolactinemia
Prolactin
Hormone secreted by the anterior pituitary
It acts directly on the mammary glands to control lactation
Hyperprolactinaemia



Elevated blood prolactin
A common cause of infertility in both sexes due to gonadal function
impairment
Early indication of hyperprolactinemia: amenorrhea & galctorrhoea
Hyperprolactinemia
Increased prolactin hormone secretion by the anterior pituitary gland.
Common causes of hyperprolactinemia
•
•
•
•
•
•
Stress
Medications e.g. estrogens intake
Primary hypothyroidism :prolactin is stimulated by  TRH
Pituitary disease
Prolactinoma: microadenoma of the pituitary cells secreting prolactin
Idiopathic hypersecretion: e.g. due to impaired secretion of dopamine that
usually inhibits prolactin release
Hyperprolactinemia
Diagnosis of the cause of hyperprolactinemia:
•
FFIRST, the followings causes should be EXCLUDED:




•
Stress
Medications intake
Primary hypothyroidism (low T3 & T4, High TSH)
Pituitary diseases (assay of other pituitary hormones)
If all above are excluded
Differential diagnosis between:
• Prolactinoma
• Idiopathic hypersecretion:
–
–
Detailed pituitary MRI (to exclude prolactinoma)
Dynamic tests of prolactin secretion:
1- Administration of TRH.
2- Then, blood prolactin (PRL) is measured:
• if PRL : Idiopathic hyperprolactinemia (caused by low dopamine)
• If no in PRL: Pituitary tumor
Polycystic Ovary Syndrome (POCS)
Polycystic ovary syndrome is a problem in which a woman’s hormone are out of balance.
It can cause irregular menstruation & may lead to infertility (due to anovulation).
Polycystic ovary syndrome (or PCOS) is common, affecting as many as 1 out of 15 women.
Often the symptoms begin in the teen years.
For reasons that are not well understood, in PCOS the hormones get out of balance.
One hormone change triggers another, which changes another.
For example, the sex hormones get out of balance. Normally, the ovaries make a tiny
amount of male sex hormones (androgens). In PCOS, ovaries produce more androgens. &
thus this may cause anovulation, menstrual disturbances, infertility, acne & grow extra facial
& body hair (hirsutism)
Review of
Synthesis of Steroid Hormones
(testosterone & estradiol) in the Ovary
LH
LH receptor
FSH
FSH receptors
cholesterol
Estradiol
aromatase
Androstendione
Theca cell
Androstendione
Testosterone
Granulosa cell of ovary
Polycystic Ovarian Syndrome (POCS)
Stimulation
of theca cells of the ovary
by LH
↑
LH
(with N. or ↓ FSH)
Anovulation
to produce androstendione
Which is converted to testosterone
in granulosa cells
Hirsutism
↑ Estradiol
↑ Free testosterone
in granulosa cells
Start here
Biochemical, Endocrinal
& Clinical
Changes in PCOS
Obesity
↓ SHBG
Insulin resistance
Polycystic Ovary Syndrome (POCS)
Polycystic Ovarian Syndrome (POCS)
• The common clinical features of PCOS are:
- Menstrual irregularities
- Signs of androgen excess (as hirsutism)
- Subfertility/Infertility (due to anovulation)
- Insulin resistance (due to obesity)
• The classical hormonal profile of PCOS is:
- Hypersecretion of LH (in 60% of cases)
- Androgen (testosterone) excess
- Normal (or low) concentration of FSH
• It is important to exclude disorders with similar presenting features as
androgen secreting tumors & CAH
Polycystic Ovarian Syndrome (POCS)
Laboratory Investigations of POCS
↓ SHBG (sex hormone binding globulin)
↑ Free Testosterone (& ↓ Total testosterone )
↑ Androgens (androstendione)
↑ LH: in 60% of cases
 Normal (or low) FSH
↑ LH/FSH ratio : in > 90% of patients
Polycystic Ovary Syndrome (POCS)
Ultrasonographic (Sonar) Diagnosis of POCS
Polycystic Ovary Syndrome (POCS)
Biochemical Aspects of Treatment of POCS
Is directed towards interrupting the cycle by
 Lowering LH levels with oral contraceptive pills
 Increasing FSH production by clomiphen
 Weight reduction in obese patients (to reduce insulin resistance)