Investigation of Infertility

OBJECTIVESOBJECTIVES

– Definition of infertility– The laboratory approach to infertility in the

women – Interpretation of results of investigation of

infertility in female and male– Understand the diagnostic approach to

infertility in male– Hyperprolactinaemia– Polycystic Ovary Syndrome

Requirements for Conception Requirements for Conception

• Production of healthy egg and sperm

• Unblocked tubes that allow sperm to reach the egg

• The sperms ability to penetrate and fertilize the egg

• Implantation of the embryo into the uterus

• Finally a healthy pregnancy

Infertility/ SubfertilityInfertility/ Subfertility

• The inability to conceive following unprotected sexual intercourse

– 1 year (age < 35) or 6 months (age >35)

Infertility EtiologyInfertility Etiology

Female FactorsFemale Factors

Female InfertilityFemale Infertility• Ovulation Disorders:• Aging• Diminished ovarian reserve• Endocrine Disorder• Polycystic Ovary Syndrome (PCOS)• Premature Ovarian Failure

• Tubal Factors:• Obstruction

– History of Pelvic Inflammatory Disease (PID)– Tubal Surgery

• Previous ectopic and salpingectomy

• Uterine/Cervical Factors:• Congenital uterine anomaly• Fibroids• Poor cervical mucus quantity/quality

– Smoking– Infection

• Primary Hypogonadism: • Radiation• Testicular Trauma• Varicocele• Orchitis• Systemic disorder

• Altered Sperm Transport:• Absent vas deferens or obstruction• Epididymal absence or obstruction• Erectile dysfunction (ED)• Retrograde ejaculation

• Secondary Hypogonadism:• Androgen/Estrogen excess• Infiltrative disorder (Sarcoid, TB)• Pituitary adenoma• Trauma

• Other medications:• Antiandrogens

Male Infertility

History & Examination

Amenorrhoea, OligomenorrhoeaNormal menses

?OvulatingMeasure [Progesterone] in day 21 (mid luteal)

Perform pregnancy test

Further tests indicated

+ ve

Measure [LH], [FSH], & [Prolactin]

High FSH. (+ LH)

>30nmol/L <10nmol/L

Ovarian failure

Ovulating Not ovulating

No further

tests required

-ve

High LHLow FSH

PCOS

High Prolactin

Further investigate hyperprolactinaemia

All Normal

*Diagnostic approach to infertility in the woman

Abnormal sperm countNormal sperm analysis, eugonadal

No endocrine tests are required Measure testosterone, gonadotrophins, and Prolactin

TestosteroneGonadotrophins

Testosterone Gonadotrophins

Testosterone Prolactin

*Diagnostic approach to subfertility in the man

History & examination

Primary testicular failureHypogonadotrophic

hypogonadism: due to hypothalamic-pituitary

disease

Hyperprolactinaemia: rare

Primary Testicular FailurePrimary Testicular Failure

• Damage to both the interstitial cells and tubules Testosterone & Gonadotrophins (LH & FSH)

• Only tubular impairment selective in FSH, while androgen may be normal (azoospermia)

• [Azoospermia with normal FSH and normal testicular volume indicates bilateral genital tract obstruction]

Evaluation of the Infertile coupleEvaluation of the Infertile couple

• History and Physical exam

• Semen analysis

• Thyroid and prolactin evaluation

• Determination of ovulation– Basal body temperature record– Serum progesterone– Ovarian reserve testing

• Hysterosalpingogram

Infertility may be caused by endocrine problems:This is common in the femaleBut rare in the male

Endocrine investigation is of diagnostic Endocrine investigation is of diagnostic value for women who have:value for women who have:

Irregular or no menstruationNo ovulation

Endocrine causes of infertility in Endocrine causes of infertility in womenwomen

• Primary ovarian failure: – postmenopausal hormonal pattern: (↑ gonadotrophins &

oestradiol) – Hormone replacement therapy can be given (this will not treat

the infertility)

• Hyperprolactinaemia• PCOS:• Cushing’s syndrome• Hypogonadotrophic hypogonadism:

– Rare– due to hypothalamic-pituitary lesion

Cushing Syndrome

• Overproduction of cortisol by the adrenal cortex

• Prolonged exposure of body Prolonged exposure of body tissues to cortisol or other tissues to cortisol or other glucocorticoidsglucocorticoids

• Causes infertility in women due to:– Increased production of androgens and

hirsutism

Prolactin and Prolactin and HyperprolactinaemiaHyperprolactinaemia

Prolactin is an anterior pituitary hormoneIts secretion is tightly regulated:

stimulated by TRH from the hypothalamusinhibited by dopamine from hypothalamus

It acts directly on the mammary glands to control lactationHyperprolactinaemia

It is elevated circulating [Prolactin]It is a common conditionIt causes infertility in both sexes due to gonadal fucntion impairement.Early indication of hyperprolactinaemia:

In women: amenorrhoea & galctorrhoeaIn men: none

Causes of hyperprolactinaemiaCauses of hyperprolactinaemia

• Stress• Drugs• e.g. oestrogens, phenothiazines,

metoclopramide, α-methyl dopa• Seizures• 1ary hypothyroidism (prolactin is stimulated by the

raised TRH)• Other pituitary disease• Prolactinoma (commonly microadenoma)• Idiopathic hypersecretion (e.g. due to imparied

secretion of dopamine that usually inhibits prolactin release.

Diagnosis of the cause of Diagnosis of the cause of HyperprolactinaemiaHyperprolactinaemia

• Exclude:– Stress– Drugs– Other disease

• Differential diagnosis:• prolactinoma or• idiopathic hypersecretion:

– Detailed pituitary imaging– Dynamic tests of Prolactin secretion:– administration of TRH, then measure serum

[prolactin]:• if : idiopathic hyperprolactinaemia,• If no rise: pituitary tumor

Polycystic Ovarian SyndromePolycystic Ovarian Syndrome

• The common features of PCOS are menstrual irregularities, signs of androgen excess, and obesity

• The classical profile of PCOS is that of hypersecretion of LH(60%), androgen excess and normal concentration of FSH

• It is imp. To exclude disorders with similar presenting features as androgen, secreting tumors and CAH

Polycystic ovarian syndrome, Polycystic ovarian syndrome, continued…continued…

Associated with:• Insulin resistance (in

50% of patients) and excessive androgen production (very common)

• Obesity (40% of cases)• Hirsutism• Chronic anovulation• Glucose intolerance• Hyperlipidemia

• Hypertension• Menstrual disorders• Hypersecretion of

leutinizing hormone (LH) and androgens

• Diagnosis done by measuringDiagnosis done by measuring:– Free testosterone (total testosterone is less

sensitive than free testosterone, androgens often increase in PCOS)

– Sex hormone-binding globulin (SHBG; often decreases in PCOS tends to↓ [total testosterone]& ↑ [free testosterone])

– Leutinizing hormone (LH; ↑ in 60% of cases)

– Follicle stimulating hormone (FSH; often normal in PCOS)

– LH/FSH Ratio (↑ in > 90% of patients)

Polycystic ovarian syndrome, Polycystic ovarian syndrome, continued…continued…

LH ↑FSH ↓

Stimulation of ovarian stroma & theca by LH

↑ Androgens & free androgens

Aromatisation in adipose tissue

↑ plasma [oestrone]

↓SHBG

Insulin resistanceObesity

Hirsutism

Anovulation

Biochemical, metabolic & Biochemical, metabolic & endocrine changes in PCOSendocrine changes in PCOS

• Treatment is directed towards interrupting the cycle by

• lowering LH levels with oral contraceptive pills,

• weight reduction in obese patients

• enhancement of FSH production by clomiphen