STATE UNIVERSITY OF MEDICINE AND PHARMACY N.

TESTEMIANU
DEPARTMENT OF OBSTETRICS AND GYNECOLOGY

INFERTILITY

CORINA CARDANIUC
 INFERTILITY. DEFINITION
World health organization ( WHO):
Infertility is the inability to conceive a child after
1 year of regular sexual intercourse, without
contraception, (in the absence of known
reproductive pathology, breastfeeding or
postpartum amenorrhoea).

Primary infertility is infertility in a couple who

have never had a child.
Secondary infertility is failure to conceive
following at least one prior conception.
INCIDENCE OF INFERTILITY

Affects both men and women

Affects approximately 15% of all couples
Varies from country to country
Worldwide ranges from 12 28%

Primary infertility 4-7%

Secondary infertility 6-13%
INCIDENCE OF INFERTILITY
According to WHO:
Female causes 25-37%
Male causes 8-22%
Both male & female 21-38%
No identified cause 5-15%

According to The Mayo Clinic, USA:

Female causes 40%
Male causes about 20%
Both male & female 30-40%
INCIDENCE OF INFERTILITY
DATA FROM UK, 2009
Pregnancy is a result of a complex chain of events
wich includes:
Ovulation release of a mature egg from the ovary
Its transport through the fallopian tube toward the uterus
Fertilization
Implantation the fertilized egg must attach to the uterine wall
So, infertility can result from problems that interfere with any of
these steps.
 ETIOLOGY OF INFERTILITY IN THE FEMALE

Common causes of infertility of females

include:

Ovulatory dysfunction (endocrine factors) 30-40%

Tubal/pelvic disease 40-50%

Uterine factors 5-10%

Cervical factors 5-10%

Unexplaind 20-30%
FEMALE INFERTILITY. OVULATORY DYSFUNCTION

PCOS
Hypothalamic-pituitary abnormalities
(hypogonadotrophic hypogonadism; idiopathic
hypothalamic hypogonadism or Kallman syndrome)
Age-related Menopausal Transition
Premature Ovarian Failure

Lutheal fase insufficiency

Thyroid disease and hyperprolactinemia may

also contribute to menstrual disturbances.
FEMALE AGING AND OVULATORY DYSFUNCTION
There is a clear inverse
relationship between female
age and fertility

After age 35 a woman's fertility

decreases rapidly

Age-related infertility is most

closely linked to the loss of
viable oocytes

A woman is born with between

two and three million oocytes
which will decrease with time
(atresia of nondominant
follicles)
PCOS
A metabolic and endocrine disorder
Anovulation
Menstrual irregularities,oligo/amenorrhea
Hirsutism
Acne
Obesity
Increased LH/FSH ratio
Raised androgens
Redused SHBG
High Insuline levels
USG 10 or more follicles of 2-10 mm in
diameter in one plaine; increased ovarian
volume
ELEVATED PROLACTIN

Also called hyperprolactinemia

Can cause:

irregular ovulation or anovulation

irregular periods
galactorrehea
OVARIAN FAILURE

Premature Ovarian Failure (POF), also known as

premature ovarian insufficiency, premature menopause,
hypergonadotropic hypogonadism, is the loss of function
of the ovaries before age 40.
The triad for the diagnosis is amenorrhea,
hypergonadotropinism, and hypoestrogenism.
Causes:
- genetic disorders (gonadal dysgenesis)
- radiation and/or chemotherapy
- hysterectomy
- prolonged GNRH therapy
TUBAL AND PELVIC FACTORS

A wide variety of etiologies may contribute to

tubal disease, including:
Endometriosis
Pelvic Inflammatory Disease
Uterine Fibroids
Pelvic Adhesions

Adhesions can prevent normal tubal movement,

the transport of the fertilized egg into the uterus.
 PID
Pelvic inflammatory disease (PID) is a spectrum of
infections of the female genital tract that includes
endometritis, salpingitis, tuboovarian abscess, and
peritonitis.
The most common causes of tubal disease are infection
with Chlamydia trachomatis or Neisseria gonorrhoeae.
Untreated PID can lead to serious consecvences including
infertility, ectopic pregnancy, and chronic pelvic pain.
 UTERINE FIBROIDS AND PELVIC ADHESIONS

Fibroids are benign tumors in

the wall of the uterus
May cause infertility by blocking
the fallopian tubes

Pelvic adhesions are bands of

scar tissue that bind organs
after pelvic infection,
appendicitis, or abdominal or
pelvic surgery
This scar tissue formation may
impair fertility
ENDOMETRIOSIS
Occurs when the uterine tissue
implants and grows outside of the
uterus, affecting the function of
the ovaries, uterus and fallopian
tubes.

Inflammation and chronic bleeding

within implants of endometriosis
can lead to obstruction of fallopian
tubes or development of severe
pelvic adhesions.

There is a 25-35% rate of infertility

in cases of endometriosis
UTERINE ABNORMALITIES

Congenital Anomalies: uterine septum,

bicornuate uterus, unicornuate uterus, and
uterine didelphys

Endometrial Polyps

Asherman Syndrome: intrauterine adhesions,

also called synechiae
CERVICAL FACTORS
Abnormalities in cervical mucus production
Anti sperm anti body

Cervical stenosis

Abnormalities in cervical mucus:

- cryosurgery
- cervical conization
- cervical infection (Chlamydia
trachomatis, Neisseria gonorrhoeae, Ureaplasma
urealyticum, and Mycoplasma hominis)
IMMUNE INFERTILITY
The woman may produce anti-sperm antibodies
(ASA) to her partners sperm.

ASA neutralize sperm by clumping them together

and destroying their membranes.

12 to 15 % of unexplained infertility in women is

linked to ASA.
ETIOLOGY OF INFERTILITY IN THE MALE
 PRE-TESTICULAR CAUSES
Pre-testicular factors refer to conditions that impede
adequate support of the testes and include situations of
poor hormonal support and poor general health
including:

Hypogonadotropic hypogonadism
Drugs, alcohol
Medications:
- chemotherapy, anabolic steroids, cimetidine,
spironolactone (affect spermatogenesis)
- phenytoin (decrease FSH levels)
- nitrofurantoin (decrease sperm motility)
TESTICULAR FACTORS
Testicular factors refer to conditions where the testes produce semen of
low quantity and/or poor quality despite adequate hormonal support
and include:
Age
Genetic defects on the Y chromosome
Abnormal set of chromosomes: Klinefelter syndrome
Neoplasm, e.g. seminoma
Cryptorchidism
Varicocele
Trauma
Hydrocele
Testicular cancer
Acrosomal defects affecting egg penetration
Idiopathic oligospermia - unexplained sperm deficiencies account for
30-40% of male infertility.
Urogenital tract infections
POST-TESTICULAR CAUSES

Post-testicular factors refer to conditions that affect the

male genital system after testicular sperm production
and include defects of the genital tract and problems in
ejaculation:
Vas deferens obstruction
Congenital absence of the vas deferens
Infection of accessory gland, e.g. prostatitis
Retrograde ejaculation
Ejaculatory duct obstruction
Hypospadias
Impotence
ANTISPERM ANTIBODIES

Antisperm antibodies may be detected in 10% of men.

These antibodies may be particularly prevalent

following vasectomy, testicular torsion, testicular
biopsy, or other clinical situations in which the blood-
testis barrier is breached.

It is currently felt that only IgG or IgA bound to the

sperm head or midpiece are critical for decreasing
fertilization capacity.
INVESTIGATIONS - MALES
History
Semen analysis

Urological examination to look for:

anatomical abnormalities
infections
endocrine disorders
varicocele
THE MALE HISTORY

Pubertal development and difficulties with sexual

function
Erectile dysfunction
Ejaculatory dysfunction
Sexually transmitted diseases or frequent
genitourinary infections, including epididymitis or
prostatitis
History of cryptorchidism
History of varicocele (dilated veins of the pampiniform
plexus of the spermatic cords that drain the testes)
THE MALE HISTORY

Prior chemotherapy or local radiation therapy

Hypertension, diabetes mellitus, and neurologic
disorders may be associated with erectile dysfunction
or retrograde ejaculation
Medications with adverse impact on semen
parameters: cimetidine, erythromycin, gentamicin,
tetracycline, and spironolactone
Cigarettes, alcohol, illicit drugs, and environmental
toxins
The use of anabolic steroids decreases sperm
production by suppressing the production of intra-
testicular testosterone
EXAMINATION OF THE MALE PATIENT

Secondary sexual characteristics: beard growth, axillary and

pubic hair
The penile urethra should be at the tip of the gland for proper
semen deposition in the vagina
Testicular length
The epididymis should be soft and nontender to exclude
chronic infection
The prostate should be smooth, nontender, and normal size.
The pampiniform plexus of veins should be palpated for
varicocele
Both vas deferens should be palpable

Further investigations of the male partner may include

endocrine tests, microbiological assessment of the semen and
imaging of the genital tract but should be initiated in the
context of a specialist infertility clinic.
SEMEN ANALYSIS. WHO REFERENCE VALUES
Volume 2.0 ml
pH 7,2-7,8
Sperm concentration 20 million/ml
Total sperm number 40 million/ejaculate
Motility 50% with progressive motility or 25% with rapid
progressive motility within 60 min after ejaculation
Morphology 30% of normal shape and form*
Viability > 75% of spermatozoa
Leukocytes < 1 million/ml
Liquefaction time: within 60 minutes
MAR test for antisperm antibodies < 50% spermatozoa with
adherent particles

The male partner should normally have two semen

analyses performed during the initial investigation.
SEMEN ANALYSIS
Oligospermia or Oligozoospermia - decreased number of
spermatozoa in semen

Aspermia - complete lack of semen

Hypospermia - reduced seminal volume

Azoospermia - absence of sperm cells in semen

Teratospermia - increase in sperm with abnormal

morphology

Asthenozoospermia - reduced sperm motility

INVESTIGATIONS - FEMALE

History
Physical examination

Post-coital test

Patency of the tubes

Looking into the uterus

Biopsy of the lining of the uterus

Measuring progesterone levels

EVALUATION OF THE INFERTILE COUPLE
The Female History:
Duration of infertility

Menstruation (frequency, duration, recent change in interval or

duration, hot flashes, and dysmenorrhea)
Dyspareunia

Prior contraceptive use

Coital frequency

History of recurrent ovarian cysts, endometriosis, leiomyomas,

sexually transmitted diseases, or pelvic inflammatory disease.
Pregnancy complications such as miscarriage, preterm delivery,
retained placenta, chorioamnionitis, or fetal anomalies.
History of abnormal Pap smears, cervical conization
EVALUATION OF THE INFERTILE COUPLE
The Female History:
Symptoms of hyperprolactinemia or thyroid disease

Symptoms of androgen excess such as acne or

hirsutism may suggest a PCOS/adrenal hyperplasia

Prior chemotherapy or pelvic irradiation may suggest

the presence of ovarian failure

Pelvic and abdominal surgeries

Medications
EVALUATION OF THE INFERTILE COUPLE
The Female History:
Social history should focus on lifestyle and
environmental factors such as eating habits and
exposure to toxins:

Cigarette smoking
Alcohol consumption

Caffeine consumption

Illicit drugs
PHYSICAL EXAMINATION OF THE FEMALE PATIENT
Vital signs
Height

Weight

Thyroid abnormalities

Hirsutism, alopecia, or acne indicates the need

to measure androgen levels.
Pelvic exam: cervical/uterine abnormalities

Breast examination
OVULATORY FUNCTION
Menstrual Pattern. Regular menstrual cycles are usually
indicative of ovulation.
Basal Body Temperature. This biphasic temperature
pattern is strongly predictive of ovulation
Ovulation Predictor Kits measure the concentration of
urinary luteinizing hormone (LH) by colorimetric assay
Serum Progesterone - on 21th day of menstrual cycle, or
7 days following ovulation. Values above 4 to 6 ng/mL
are highly correlated with ovulation and subsequent
progesterone production by the corpus luteum
Endometrial Biopsy.
Sonography. Serial ovarian sonography can demonstrate
the development of a mature follicle and its subsequent
collapse during ovulation.
INVESTIGATIONS
Early follicular phase estimation of FSH and LH
is only performed if clinically indicated
An elevated basal day-three FSH is correlated
with diminished ovarian reserve in women aged
over 35 years

There is no value in measuring thyroid function or

prolactin in women with a regular menstrual cycle,
in the absence of galactorrhoea or symptoms of
thyroid disease.
INVESTIGATIONS. TUBAL PATENCY.

The female partner should normally have a test of tubal

patency during the initial investigation of infertility

A hysterosalpingogram may be used as a screening test

for tubal patency in low risk couples

When an evaluation of the pelvis is required, however, a

diagnostic laparoscopy with dye transit is the procedure
of choice

Before undergoing uterine instrumentation women

should be offered screening for Chlamydia trachomatis
HYSTEROSALPINGOGRAPHY
Hysterosalpingography is generally performed on cycle
day numbers 5 through 10.
Hysterosalpingography is useful for evaluating the
shape and size of the uterine cavity, and tubal status .
Hysterosalpingography also provides analysis of the
contour of the intrauterine cavity.
A polyp, leiomyoma, or adhesion within the cavity will
resulte in an intrauterine "defect" in dye opacity on
radiograph.
Hysterosalpingography can also define developmental
uterine anomalies
Normal HSG closed tubes on HSG
Bicornuate uterus Didelphys uterus
FALLOPOSCOPY

Falloposcopy is defined as transvaginal

microendoscopy of the fallopian tubes and
direct visualisation of the entire fallopian tube
lumen.
LAPAROSCOPY

Laparoscopy is the gold standard approach for

the assessment of pelvic pathology.
Chromotubation may be performed.
Indigo carmine dye is preferable to methylene
blue, as the latter rarely may induce acute
methemoglobinemia, particularly in patients
with glucose-6-phosphate dehydrogenase
deficiency.
Laparoscopy allows both diagnosis and
immediate surgical treatment of abnormalities
such as endometriosis or pelvic adhesions.
Normal tube and ovary Pelvic adhesions
Bicornuate Uterus Endometriosis
Policistic ovary Hidrosalpinx
HYSTEROSCOPY
Endoscopic evaluation of the intrauterine cavity
is the primary method for defining intrauterine
abnormalities.
POSTCOITAL TEST
Also known as the Sims-Huhner test
The test is performed to evaluate the presence
of normal cervical mucus.
A couple is requested to have intercourse on the
day of ovulation.
A sample of the cervical mucus is obtained from
the cervical os within a few hours.
At least 10 motile sperm per high-power field
should be visible under the microscope.
MANAGEMENT
GENERAL ADVICE TO THE COUPLE

Lifestyle modification
Sexual intercourse every 2-3 days

Smoking

Alcohol

A body mass index

HYPERPROLACTINEMIA

Dopamine agonists are the primary treatment

of hyperprolactinemia.
Surgical therapies should only be considered
with prolactin-secreting adenomas resistant to
medical therapy.
Bromocriptine 2,5 mg x 2 daily
Carbegoline (Dostinex)
OVULATION INDUCTION
Clomiphene citrate (CC) is the initial treatment
for most anovulatory infertile women.
Estrogen antagonist.

As a result, estrogen-negative feedback is

interrupted centrally and follicle-stimulating
hormone (FSH) secretion increases from the
anterior pituitary, leading to maturation of
multiple follicles.
OVULATION INDUCTION
Clomiphene citrate is administered orally,
typically starting on the third to fifth day after
the onset of spontaneous or progestin-induced
menses.
The effective dose of CC ranges from 50 mg/d
to 250 mg/d, although doses in excess of 100
mg/d are not approved.

Ovulation induction with clomiphene should

only be performed in circumstances which
allow access to ovarian ultrasound monitoring.
 METFORMIN
Metformin is an oral biguanide insulin-
sensitising agent widely used for the treatment
of type-2 diabetes.
These compounds act to increase target tissue
responsiveness to insulin, thereby reducing
compensatory hyperinsulinemia
Metformin in combination with clomifene citrate
is effective in inducing ovulation
GONADOTROPINS
FSH and hMG are both effective for ovulation induction
in women With clomiphene-resistant polycystic ovarian
syndrome (PCOS).
Most clinicians begin ovulation induction attempts at a
low dosage (50 to 75 IU/d) of gonadotropins and
gradually increase the dose if no ovarian response (as
assessed by serum estradiol measurements) is noted
after several days. This is referred to as a "step-up"
protocol.
Humegon (75U FSH, 75 U LH) (Organon-Holland)
Pergonal (75U FSH, 75 U LH) (Ares-Serono-Swistzerland)
Menogon (75U FSH, 75 U LH) (Ferring-Germany)
Metrodin (75U FSH) (Ares-Serono- Swistzerland)
Puregon (100U FSH)) (Organon-Holland)
Gonal F (75U FSH) (Ares-Serono- Swistzerland)
GNRH
The pulsatile administration of gonadotrophin-
releasing hormone is an effective treatment for
women with anovulation due to hypothalamic factors.
COMPLICATIONS OF FERTILITY DRUGS
Ovarian hyperstimulation syndrome (OHSS) is an
exaggerated response to ovulation induction therapy.
Tipically is associated with exogenous gonadotropin
stimulation.
Symptoms may include abdominal pain and
distension, ascites, gastrointestinal problems,
respiratory compromise, oliguria, hemoconcentration,
and thromboembolism.
Development of OHSS involves increased vascular
permeability with loss of fluid, protein, and electrolytes
into the peritoneal cavity, and leads to
hemoconcentration.
 Ovarian hyperstimulation syndrome

Table 20-5 Classification and Staging of Ovarian Hyperstimulation Syndrome

Grade 1: Abdominal distention/discomfort

Grade 2: Grade 1 plus nausea and vomiting or diarrhea
Ovaries enlarged 512 cm
Grade 3: Sonographic evidence of ascites
Grade 4: Clinical evidence of ascites or hydrothorax or difficulty breathing
Grade 5: All of the above plus decreased blood volume, hemoconcentration, diminished renal
perfusion and function, and coagulation abnormalities

From Whelan, 2000, with permission.

OVARIAN DRILLING
Surgical methods of ovulation induction for women with
clomifene citrate-resistant PCOS include laparoscopic ovarian
drilling with diathermy.

This technique is designed to create multiple perforations in the

ovarian surface and stroma.

The procedure destroys ovarian androgen-producing tissue and

reduce peripheral conversion of androgens to estrogens.

A fall in serum levels of androgens and LH, and an increase in

FSH levels
 Policystic ovary ovarian drilling
TUBAL INFERTILITY
Proximal and midtubal occlusion can be treated with either tubal
reanastomosis or IVF
If pregnancy has not occurred within 12 months of tubal surgery,
IVF should be discussed .

Surgical reanastomosis of fallopian tube segments.

DISTAL TUBAL OBSTRUCTION
In these cases, neosalpingostomy can be
performed at laparoscopy.
The risk of ectopic pregnancy is high, the
likelihood of pregnancy is 50 percent or lower, and
postoperative re-occlusion is common.
Hydrosalpinges that are dilated more than 3 cm in
diameter, that are associated with significant
adnexal adhesions yield a poor prognosis.
These tubes are best treated by salpingectomy
and plans for IVF.
If both tubes are affected, bilateral salpingectomy
is recommended prior to proceeding with IVF.
NEOSALPINGOSTOMY.
CORRECTION OF UTERINE FACTORS

Myomectomy can be performed using

hysteroscopy, laparoscopy, or via laparotomy,

Endometrial Polyps - hysteroscopic polypectomy

Intrauterine adhesions - hysteroscopic

adhesion resection
TREATMENT OF ENDOMETRIOSIS
Medical management (ovarian suppression) ovulation
suppression agents: (medroxyprogesterone,
gestrinone, combined oral contraceptives and GnRHa)
Surgical ablation or resection of endometriosis
plus laparoscopic adhesiolysis

In cases of moderate and severe endometriosis,

assisted reproduction techniques should be
considered as an alternative to, or following
unsuccessful surgery.
Surgical ablation of endometriosis
ADHESIONS

minimally invasive surgery may help decrease

adhesion formation.
 Pelvic adhesions
 Adeziolysis Cromopertubation
 After adheiolysis
ASSISTED REPRODUCTION

The most common techniques used are:

Intrauterine Insemination
In-vitro fertilisation
Intracytoplasmic sperm injection

The women should be less than 40 years old and

in good health
INTRAUTERINE INSEMINATION
This technique processes semen and
separates motile, morphologically normal
spermatozoa from dead sperm,
leukocytes, and seminal plasma.
This highly motile fraction is then inserted
transcervically via a flexible catheter near
the anticipated time of ovulation.
Intrauterine insemination can be
performed in natural (unstimulated)
cycles or following stimulation of the
ovaries and is appropriate therapy for
treatment of cervical factors, mild and
moderate male factors, and unexplained
infertility.
ASSISTED REPRODUCTIVE TECHNOLOGIES
These techniques include:
- in vitro fertilization (IVF)
- intracytoplasmic sperm injection (ICSI)
- egg donation
- gestational carrier surrogacy
- gamete intrafallopian transfer (GIFT)
- zygote intrafallopian transfer (ZIFT).
IN VITRO FERTILIZATION
During IVF, mature oocytes from stimulated
ovaries are retrieved transvaginally with
sonographic guidance.
Sperm and ova are combined in vitro to prompt
fertilization.
Viable embryos (Blastocysts) are transferred
transcervically into the endometrial cavity using
sonographic guidance.
IVF should be considered as the first line
treatment for moderate to severe tubal disease
IN VITRO FERTILIZATION
INTRACYTOPLASMIC SPERM INJECTION
This variation on IVF is most applicable to male
factor infertility.
During the ICSI, cumulus cells surrounding the
ova are enzymatically digested, and a single
sperm is directly injected through the zona
pellucida and oocyte cell membrane.
IVF and ICSI are effective treatments for men
with moderate to severe semen abnormalities
EGG DONATION

Egg donation may be employed in cases of

infertility associated with ovarian failure or
diminished ovarian reserve.

The technique may also be used to achieve

pregnancy in fertile women wich are at risk for
maternally transmitted genetic disease.
GAMETE INTRAFALLOPIAN TRANSFER

Eggs and sperm are placed via catheter through

the fimbria and deposited directly into the
oviduct.

This transfer of gametes is most commonly

performed at laparoscopy.

GIFT is most applicable for unexplained infertility

and should not be considered for tubal factor
causes of infertility.
ZYGOTE INTRAFALLOPIAN TRANSFER

Embryo transfer is not performed directly into

the uterine cavity, but rather into the fallopian
tube at laparoscopy.
REFERENCES

Williams Gynecology Copyright 2008