1. Biochemical Aspects of Male & Female Subfertility/ Infertility

2. 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.

3. 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

4. Infertility/ Subfertility
The inability to conceive
following unprotected sexual intercourse
for 1 year (age < 35)
or 6 months (age >35)

5. Infertility Etiology Female Factors: 35% Unexplained: 28%
Other: 13%
Some sources list female factors
as high as 50%
Female Factors Breakdown:
Ovarian Dysfunction: 21%
Tubal Factors: 14% 5

6. 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)

7. Spirnolactone antihyperstensive
Cimetidine : antiacid

8. Galactorrhoea (inappropriate breast milk production; i. e
Galactorrhoea (inappropriate breast milk production; i.e. in the absence of pregnancy most commonly caused be hyperprolactinaemia)
Hirsutism (an increase in body hair with male pattern distrubutuon

9. LABORATORY Diagnostic Approaches of Male Infertility Seminal Fluid Analysis Hormonal Assay

10. 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
% Ejaculate
Source of Secretion
5 %
Testis
40 – 80 %
Seminal vesicles
13 – 33 %
Prostate
2 - 5 %
Bulbo-urethral & urethral glands

11. Laboratory Seminal Fluid Analysis
Physical Analysis
Volume
Liquefaction time (after coagulation) pH
Microscopic Analysis
Sperm count
Sperm morphology
Sperm motility
Sperm viability
Sperm agglutination
Biochemical Analysis
Fructose test
Acid phosphatase
Others
Antisperm antibody

12. 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

13. Diagnostic Approach to Infertility in Males
Other Anomalies
Abnormal Forms
Sperm Agglutin.
Antobodies
Pus cells
RBCs
Seminal Fluid Analysis
Normal Sperm Analysis
Low Sperm Count
NORMAL
Hormonal
Profile
No endocrine tests are required
Testosterone
FSH & LH
Prolactin
Prostate
Abnormal Profile
Seminal
Vesicle
&
Ejacul. Duct
Vas
Deference
Obstruction
Vasectomy
Trauma
Congenital Absence
* Lecture Notes on Clinical Biochemistry
In both men & women infertility a serum [FSH] > 25U/L indicates primary gonadal failure
Prostatic Invest.
Acid Phosphatase
PSA
FSH & LH
 Testosterone
Testosterone
 FSH & LH
Testost.
 Prolactin
Secondary
hypogonadism
Primary
hypogonadism
(e.g. testicular)
Hyperprolactinemia
Low Semen Amount
Low or no Semen Coagulation
Low Semen pH
Low Sperm Motility & Viability
Low Semen Fructose
Hypothalamic
or Pituitary
Disease
Causes ??
Orchitis, Radiation, Trauma

14. 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)

15. 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

16. 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

17. LABORATORY Diagnostic Approaches of Female Infertility Hormonal Assay

18. 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

19. Diagnostic Approach to Infertility in Females
Detailed History & Physical Examination
Normal menses
Amenorrhea, Oligomenorrhoea
No Further Tests
Investigations for Ovulation
Progesterone n day 21 (mid luteal)
Pregnancy Test
+ ve
-ve
>30 nmol/L
<10 nmol/L
*Lecture Notes on Clinical Biochemistry
Investigations depend on the phase of the menstrual cycle
Elevated serum [progesterone] at day 21 of the menstrual cycle indicates that ovulation has occurred
LH, FSH & Prolactin
Ovulation
No Ovulation
High Prolactin
Low FSH & LH
High FSH
& LH
High LH
Low FSH
All Normal
Further
Investig.
Pituitary or hypothalam.
1ry
Ovarian Failure
Investigation for a cause of hyperprolactinemia
PCOS

20. Endocrine causes of infertility in Females
Endocrine investigation is of diagnostic value for women who
have:
Irregular or no menstruation
No ovulation

21. 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

22. Cushing Syndrome
Overproduction of cortisol by the adrenal cortex mainly caused by adrenal cortical adenoma
Due to increased production of adrenal cortical androgens (androstendione)

23. Hyperprolactinemia Prolactin Hyperprolactinaemia
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

24. 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

25. 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

26. 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)

27. Review of Synthesis of Steroid Hormones (testosterone & estradiol) in the Ovary
Theca cell
Granulosa cell of ovary LH
LH receptor
cholesterol
Androstendione
Androstendione Testosterone
FSH
aromatase
Estradiol
FSH receptors

28. Polycystic Ovarian Syndrome (POCS)
↑ LH
(with N. or ↓ FSH)
Stimulation
of theca cells of the ovary by LH
to produce androstendione
Which is converted to testosterone in granulosa cells
Anovulation
Hirsutism
Treatment of PCOS: try to break the cycle
↑ Estradiol
in granulosa cells
↑ Free testosterone
Start here
↓ SHBG
Biochemical, Endocrinal & Clinical
Changes in PCOS
Obesity
Insulin resistance

29. Polycystic Ovary Syndrome (POCS)

30. 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 )

31. 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

32. Polycystic Ovary Syndrome (POCS)
Ultrasonographic (Sonar) Diagnosis of POCS

33. 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)