Transcript Infertility (2).

Dr.Sumeya Ghanawy
Background
Definition:
Infertility = “failure to conceive following 1
year of unprotected intercourse if under 35
years of age or six months if over 35”.
10-15% couples affected
 Etiology

 Couples:
○ 16% Tubal and pelvic pathology
○ 21 % Male problems
○ 29% Ovulatory dysfunction
○ 18% Unexplaine
○ 7% Endometriosis,2%Cervical,3%Uterine,4%Multiple
For a woman with a normal menstrual cycle of 28 days,
ovulation occurs around day 14. The average survival time of
the oocyte is around 24 hours, while after ejaculation sperm may
survive for up to 7 days in the female reproductive tract.
In the general population, up to 90 per cent of couples will have
conceived after regular unprotected intercourse for three years
Several general factors may adversely affect the natural
conception rate. These are:
• Age: natural conception declines significantly in
the female after 35 years of age. This is due to the
decline in oocyte quality and numbers.
• Smoking: reduces fertility in females and semen
quality in males.
Drugs:
• non-steroidal anti-inflammatory drugs (inhibit
ovulation); • chemotherapy (destroys rapidly dividing cells
e.g. gametes);
• cimetidine, sulphasalazine, androgen injections
(affects sperm quality).
• Occupational hazards: exposure to chemicals and
radiation adversely affects male and female fertility.
Background

Normal couple:
 25-30% chance of pregnancy per ovulatory
cycle
Primary -Couple has never conceived
 Secondary -couple has had at least one
prior conception

Infertility
Time of Exposure
3 months
6 months
1 year
18 months
% Pregnant
60%
70%
85%
90%
Approach to Infertility
DDX
 Hx
 Tests/Inv
 Dx
 Rx

Approach to Infertility
Causes
Male
 Female
 Combined
 Unexplained

Male Infertility
Anatomy of the
testis
Hypothalamic-Pituitary-Gonadal Axis
Male Infertility
 Hypothalamus
○ Congenital abnormalities of hypothalamus
 e.g. Kallman’s syndrome
○ Starvation, stress or severe illness
○ Tumors (craniopharyngioma, metastatic tumor)
○ Head injury
○ Inflammation (sarcoidosis)
○ Infection (tuberculosis)
○ XRT
○ Drugs: marijuana,
Male Infertility
 Pituitary
○ Endocrine: thyroid, prolactin
○ Tumors
○ Inflammation: sarcoidosis, meningitis
○ Infiltration
○ Infarction
○ Trauma/XRT
○ Drugs: anabolic steroids
Male Infertility
 Testes:
○ Congenital: Klinefelters (XYY), developmental
disorders
○ Disorders of gonadal steroidgenesis
○ Infection: chlamydia, prostatitis, mumps orchitis
○ Autoimmune
○ Cryptorchidism
○ Tumors; chemo/XRT
○ Drugs / alcohol
○ Vascular: testicular torsion
Male Infertility
 Temperature
○ Rise in scrotal temperature
○ Occupation
○ Varicocoele
Male Infertility
Post testicular causes:
Impotence/Ejaculation
A-Neurogenic: medications (α-blockers,
methyldopa)
B-Endocrine: diabetes
○ Congenital: absence vas deferens (CF)
○ Genetic: cystic fibrosis
○ Primary ciliary dyskinesia: Kartagener syndrome
○ Hypospadia
○ Vasectomy
Male Infertility

History:










Previous children
Infections: prostatitis, STD, mumps orchitis
Trauma to head or testicles
Surgery to testicles or hernia
Occupation (sitting, bio hazards, XRT)
Chemo or Radio therapy
Ethanol or Smoking
Medication
Medical history (DM, HTN)
Previous investigations
Male Infertility

Physical
 Anatomy (meatus)
 Testicular size
 Varicocele (valsalva)
 Rectal exam (protatitis, discharge)
Male Infertility

Investigations:
 semen analysis
○ Abstain 2-7 days prior
○ At least 2 samples over different period of
time
 If abnormal:
○ Blood work: FSH, LH, TSH, testosterone, PRL
○ Testicular U/S
○ Chromosomal analysis
Semen
also known as seminal fluid, is an organic fluid that may
contain spermatozoa. It is secreted by the gonads ( testis and
accessory sex glans). Seminal fluid contains several
components besides spermatozoa: proteolytic and other
enzymes as well as fructose are elements of seminal fluid which
promote the survival of spermatozoa, and provide a medium
through which they can move or "swim".

Male Infertility

Semen analysis: Macroscopical characteristics:
Liquefaction time:
Liquefaction time is a natural change in the consistency
of semen from a semi liquid to a liquid. Immediate coagulation is
due to a clot formation from seminal vesicles material, followed
by gradual liquefaction over the next 5-20 minutes due to
enzymatic process involving the prostatic secretion. In evaluation
of liquefaction, ejaculate is placed in an incubator at 37°C and
allowed to be liquefied. Liquefaction time more than 60 minutes
or no liquefaction longer is pathologic showing lack of prostatic
enzyme or inadequate prostate function .
. Semen viscosity:
Normal semen has a viscous texture. Increase in viscosity may
occur due to hypofunction of seminal vesicles. High viscosity may affect
sperm motility and concentration. Increase in viscosity may reduce the
success of intrauterine insemination (IUI) and in vitro fertilization (IVF) .
. Appearance of the ejaculate:
A
normal
ejaculate
has
a
homogenous
grey-opalescent
appearance (WHO 2010).A whitish colour may indicate high sperm
numbers or presence of leukocytes a yellowish appearance and
purulent smell indicate infections. A reddish-brown colour indicates the
presence of red blood cells (hemospermia) .
Semen volume:
The lower reference limit for semen volume is 1.5 ml (WHO 2010).
A small volume may also be due to loss of part of the specimen,
retrograde ejaculation, abnormality or infection of accessory sex glands,
or ejaculatory duct obstruction. An extremely high volume may indicate
inflammation or urine contamination and is associated with lower
conception rates .
Semen pH:
The pH of semen reflects the balance between the pH values of the
different accessory gland secretions, mainly the alkaline seminal
vesicular secretion and the acidic prostatic secretion. A lower threshold
value is 7.2(WHO 2010). To test the pH, pH paper range 6.1 to 10.0 is
used. Whatever type of pH paper is used for this analysis, its accuracy
should be checked against known standards before the use in routine
Microscopic characteristics

Agglutination

Agglutination of spermatozoa means that motile spermatozoa stick
to each other, head to head, midpiece to midpiece, tail to tail, or mixed,
e.g. midpiece to tail. The adherence of either immotile or motile
spermatozoa to mucus threads, to cells other than spermatozoa, or to
debris is not considered agglutination and should not be recorded as
such. The presence of agglutination is suggestive of, but not sufficient
evidence to prove the existence of an immunological factor of fertility.
When agglutination is observed, semen cultures and antibody
assessment should be performed .
The major types of agglutination (WHO 2010):

grade 1: isolated <10 spermatozoa per agglutinate, many free
spermatozoa.

grade 2: moderate 10–50 spermatozoa per agglutinate, free
spermatozoa.

grade 3: large agglutinates of >50 spermatozoa, some spermatozoa
still free.

grade 4: gross all spermatozoa agglutinated and agglutinates
interconnected.
Sperm count and concentration
According to WHO2010, the lower reference limit for sperm concentration is
15 × 106 spermatozoa per ml and the lower reference limit for total sperm
number is 39 × 106 spermatozoa per ejaculate. A sperm concentration of less
than this value is regarded as abnormal .
Sperm motility
The percentage of motile spermatozoa and their progressiveness usually
give a good indication on sperm quality and are important in predicting men
fertility . Several studies have demonstrated the correlation of motility with the
fertilization rate in vivo and in vitro .

Categories of sperm movement (WHO 2010):
A simple system for grading motility is recommended that distinguishes
spermatozoa with progressive or non-progressive motility from those that are
immotile. The motility of each spermatozoon is graded as follows:

Progressive motility (PR): spermatozoa moving actively, either
linearly or in a large circle, regardless of speed.

Non-progressive motility (NP): all other patterns of motility with an
absence of progression, e.g. swimming in small circles, the flagellar
force hardly displacing the head, or when only a flagellar beat can
be observed.

Immotility (IM): no movement ().
Lower reference limit (WHO 2010):

The lower reference limit for total motility (PR + NP) is 40%.

The lower reference limit for progressive motility (PR) is 32%.
Sperm morphology
Many authors have gone as far as to argue that sperm morphology
is a reflection of sperm functional competence and Sperm morphology
assessment has been considered a valuable and stable method for
predicting the in vivo and in vitro sperm fertilizing ability .
Abnormalities of spermatozoa can be classified into head
abnormality, neck/midpiece abnormality, tail abnormality, or the
presence of cytoplasmic residue. These abnormalities can occur as a
single defect or in a combination of two, three or all four abnormalities
simultaneously. The reference value for normal sperm morphology
determined by Kruger is >14% WHO1999 vs. 2010 the WHO reference
values for normal sperm morphology is >4% .
Sperm vitality
It is especially important for samples with less than about 40%
progressively motile spermatozoa. The lower reference limit for
vitality (membrane-intact spermatozoa) is 58 %( WHO 2010).
Nowadays, there are several standard tests available for the
assessment of the vitality of spermatozoa . One of these tests is
based on the principle that dead spermatozoa take up the
supravital red stain of eosin-Y, whereas living cells, regardless of
their motility stage, will be unstained This assay reflects sperm
membrane integrity, particularly the head region which takes up
the red stain immediately
Round cell count (cells other than spermatozoa)
The existence of round cells in human ejaculates is common.
These can be immature germ cells or somatic cells including epithelial
cells of the post-testicular tract and leucocytes . Epithelial cells are
indicative of poor collection when present in high numbers . Leukocytes
are the most significant non sperm cellular elements in the semen and
are a frequent finding in patients who have unexplained infertility. A
threshold for classification of leukocytospermia as high as 1×106/ml
.The semen sample with <5 round cells/ HPF was considered normal
(WHO, 2010).
Endocrine Tests
The endocrine assessment of an infertile man includes measurements
of serum testosterone, luteinizing hormone (LH), and follicle-stimulating
hormone (FSH), and perhaps other tests:

Serum Testosterone

Measurement of a morning serum total testosterone is usually
sufficient. In men with borderline values, the measurement should
be repeated and measurement of serum-free testosterone may be
helpful.

Serum Luteinizing Hormone and Follicle-Stimulating Hormone

When the serum testosterone concentration is low, high serum FSH
and LH concentrations indicate primary hypogonadism and values
that are low or normal indicate secondary hypogonadism.
Other Hormones

Serum prolactin should be measured in any man with a low
serum testosterone concentration and normal to low serum
LH concentration. Although inhibin assays are not widely
available outside of research laboratories, low serum inhibin
concentrations may be an even more sensitive test of primary
testicular dysfunction than high serum FSH concentrations,
provided the assay is specific for inhibin B.
TERMINOLOGY

Oligozoospermia;
sperm conc. less than 15 × 106
spermatozoa per ml

Teratozoospermia; normal sperm morphology is <4% kruger
strict criteria
 Asthenozoospermia;
total motility (PR + NP) < 40% or
progressive motility (PR) < 32%.


Azoospermia; no sperm in ejaculate
Aspermia; no semen
Male Infertility

Tx / Interventions:
 Treat underlying causes
 Intrauterine Insemination (IUI)
 Intracytoplasmic Sperm Injection (ICSI)
TREATMENT
Treatment of male infertility involves the couple.

Specific endocrine treatment is available for men whose infertility
results from hypogonadotropic hypogonadism. Hypogonadotropic
hypogonadism due to hyperprolactinemia can often be corrected
and fertility restored by lowering the serum prolactin concentration. If
the hyperprolactinemia results from a medication, as is often the
case, that medication should be discontinued, if possible. The
hyperprolactinemia is caused by a lactotroph adenoma. It should be
treated with a dopamine agonist, such as cabergoline or
bromocriptine. The process of spermatogenesis normally takes 3
months. As a result, restoration of a normal sperm count usually
does not occur for at least 3 and sometimes 6 months or more after
the serum prolactin and testosterone concentrations have returned
to normal.

In some patients, who have a lactotroph macroadenoma, the
hypogonadotropic hypogonadism appears to be the result of
permanent damage to the gonadotroph cells by the mass effect of
the adenoma. Gonadotropin treatment should be instituted for these
patients.



Gonadotropin therapy: Treatment is initiated with human chorionic
gonadotropin (hCG), 1,500–2,000 IU three times per week
subcutaneously or intramuscularly for at least 6 months. hCG has
the biologic activity of LH. The hCG dose should be adjusted upward
according to symptoms of hypogonadism, serum testosterone
concentrations, and semen parameters.
Some patients with acquired hypogonadotropic states can be
stimulated with hCG alone to produce sufficient sperm. If after 6–9
months the patient remains azoospermic or severely oligospermic,
then human menopausal gonadotropin (hMG) or recombinant FSH
should be added.
• Pulsatile GnRH treatment: Pulsatile subcutaneous or intravenous
treatment with GnRH has also been successfully used to treat
gonadotropin deficient patients. GnRH has to be delivered in pulses
using a portable pump with an attached catheter and needle for
many months or years; most patients find it inconvenient to use
GnRH therapy for so long.
Genital infection

Infertile men rarely present with symptoms or signs of acute
genital infections or prostatitis, but they are sometimes
diagnosed as having infections of the urogenital tract by the
presence of increased leukocytes in the semen. Despite the
absence of symptoms, we typically treat patients who have
leukospermia, even if the culture is negative, with at least a
10-day course of antibiotics such as erythromycin or
trimethoprim-sulfamethoxazole. A second course of therapy is
usually given if leukocytes persist in the semen after
antibiotics.
Sperm Autoimmunity


Continuous or intermittent high doses of prednisone (from 40 mg/
day to 80 mg/day) for up to 6 months have been shown in placebocontrolled trials to improve cumulative pregnancy significantly in
partners of men with sperm autoantibodies.
However, many patients cannot tolerate this regimen because of the
adverse effects of high-dose corticosteroid therapy. As a result, most
couples prefer to try an assisted reproductive technique, such as
ICSI, as primary treatment for sperm autoimmunity.
Empirical Therapy


Many treatments have been used empirically for male
infertility, including clomiphene citrate and other hormones
and vitamins.
Aromatase inhibitors may improve sperm concentrations in
men with severe oligozoospermia or azoospermia prior to
sperm retrieval for ICSI.
Female Infertility

Fecundability: probability of achieving a
pregnancy within 1 menstrual cycle (25%)

Fecundity: ability to achieve a live birth within 1
menstrual cycle (6%)
Female Infertility
Female Fertility
Causes
 Hypothalamus
 Pituitary
 Ovary
 Uterus
 Vagina
 Fallopian tube
 Cervix
Hypothalamic-Pituitary-Gonadal Axis
Female Infertility

Pituitary:




Sheehan syndrome
Tumors: Pituitary adenoma, metastatic
Empty sella syndrome
Inappropriate gonadal steroid feedback:
○ estrogen excess: obesity/ tumors
○ estrogen deficiency: aromatase deficiency/ ER gene
mutation
○ androgen excess: adrenal or ovarian
○ PCOS
 Testicular feminization (46 XY) - absence
androgen receptors
Female Infertility

Hypothalamus:
 Stress
 Exercise
 Eating disorders
 Psychogenic
 Congenital/genetic: Kallman’s syndrome (hyposmia &







hypoplasia olfactory lobes of brain)
Starvation/stress or severe illness
Tumors (craniopharyngioma, metastatic tumor)
Head injury
Inflammation (sarcoidosis)
Infection (tuberculosis)
XRT
Drugs
Female Infertility

Ovary
 Gonadal dysgenesis - Turner’s Syndrome
45XO or mosaics 46 XX/45 XO
 Testicular feminization
 XRT / Chemo for childhood malignancies
 Premature ovarian failure
Female Infertility
Uterine abnormalities
 Mullerian Agenesis: Mayer-Rokitansky-
Kuster-Hauser syndrome
 Asherman’s syndrome
 Leiomyoma
 Luteal phase deficiency
Female Infertility
 Vaginal septum
 Tubal Disease
○ Infections/ STD/PID
○ Ruptured appendix
○ Septic abortion
 Endometriosis
 Cervical
Female Infertility

History:
 Age
 Regulatory of period
 Prolactin S/S
 Thyroid S/S
 Infections, Surgeries
 Medication, Smoking, Ethanol
 Medical history
 Previous investigations
Female Infertility

Examination:
 Thyroid
 Breast (milk)
 Abdomen (masses, scars)
 Vaginal (abnormalities)
 Bimanual (Uterus, masses)
Investigations
 Blood work:



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

TSH
PRL
D3 FSH
D3 LH
Luteal phase Progesterone
Imaging:
 Pelvic Ultrasound
 HSG

Diagnostic
 Laparoscopy (later)
 Cervical(post coital test)
Marker of ovarian reserve
In the ovary, anti-Müllerian hormone (AMH) is produced by the
granulosa cells. AMH levels can be measured in blood and are
shown to be proportional to the number of small antral follicles.
In women, serum AMH levels decrease with age and are
undetectable in the post-menopausal period. AMH levels
represent the quantity of the ovarian follicle pool and are a
useful marker of ovarian reserve. AMH measurement can also
be useful in the prediction of the extremes of ovarian response
to gonadotrophin stimulation for in vitro fertilization, namely poor
and hyper-response.
Ovulation testing
Various methods of predicting fertility exist, to either aid
or avoid pregnancy.
Stretch test
Cervical mucus becomes clear and stretchy during
the fertile window, to allow sperm to survive in and travel
through it.
Ovulation Prediction Kit
Ovulation prediction kits are usually antibody tests for luteinising
hormone, which peaks in urine around the time of ovulation.
Cervical position
The cervix becomes soft, high, open and wet during the
fertile window.
Basal body temperature
Basal body temperature changes during the menstural
cycle. Progesterone released during the menstrual cycle causes
an abrupt increase in basal body temperature by 0.5°C at the
time of ovulation.This enables identification of the fertile window
through the use of commercial thermometers. •
Progesterone level
measurement of progesterone in the second half of the cycle to
help confirm ovulation
Treatment
Treat the underlying cause
 Medical
 Surgical

Medical treatments
Drugs
• Clomiphene
• Human menopausal gonadotropin, hMG
• FSH
• Human chorionic gonadotropin, hCG
• Gonadotropin – releasing hormone (GnRH) analogs
• Aromatase inhibitors
• Metformin
• Bromocriptine
Gonadotropin-releasing hormone
Either Gonadotropin-releasing hormone (GnRH) or
 any Gonadotropin-releasing hormone agonist (i.e. Lupron)
may be

used. GnRH stimulates the release of gonadotropins (LH and
FSH) from the anterior pituitary in the body.

Clomiphene

is a selective estrogen receptor modulator (SERM). It is the
most widely used fertility drug. It is used as an ovarian
stimulator by inhibiting the negative feedback of estrogen at the
hypothalamus. As the negative feedback of estrogen is inhibited,
the hypothalamus secretes GnRh which in turn stimulates the
anterior pituitary to secrete LH and FSH which help in ovulation.
Aromatase inhibitors
Although primarily a breast cancer treatment, aromatase
inhibitors can also work as fertility medication, probably
through a mechanism similar to clomiphene.
Gonadotropins
Gonadotropins are the hormones in the body that normally
stimulate the gonads (testes and ovaries). For medication, they
can be extracted from urine or by genetic modification.
For example, the so-called menotropins consist
of LH and FSH extracted from
human urine from menopausal women. FSH and FSH
analogues are mainly used for ovarian hyperstimulation as well
as reversal of anovulation.
There are also recombinant variants which are created by
inserting the DNA coding for it into bacteriae. The bacterial DNA
is then called Recombinant DNA. Examples of recombinant FSH
are Follistim and Gonal F, while Luveris is a recombinant LH.
Human chorionic gonadotropin

Human chorionic gonadotropin (hCG) is normally produced
during pregnancy. However, it can also replace LH as
an ovulation inducer.

Others

dopamine agonist, such as cabergoline or bromocriptine. For
treatment of hyperprolactinaemia

Metformine in PCOS
COMPLICATIONS
Fertility drugs have the risk of multiple pregnancies
• Injectable fertility drugs increase the chance of
multiple births
• Careful monitoring: blood tests, hormone tests,
ultrasound measurement of ovarian follicle size
Because of risk of ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome (OHSS)
is a medical condition affecting the ovaries of some
women who take fertility medication to stimulate egg
growth. Most cases are mild, but rarely the condition
is severe and can lead to serious illness or death.
OHSS is divided into the categories mild, moderate, severe, and
critical. In mild forms of OHSS the ovaries are enlarged (5–
12 cm) and there may be additional accumulation of ascites with
mild abdominal distension, abdominal pain, nausea, and
diarrhea. In severe forms of OHSS there may
be hemoconcentration, thrombosis and
distension,oliguria (decreased urine production), pleural
effusion, and respiratory distress. Early OHSS develops
before pregnancy testing and late OHSS is seen in early
pregnancy.
Symptoms

Symptoms are set into 3 categories: mild, moderate, and
severe. Mild symptoms include abdominal bloating and
feeling of fullness, nausea, diarrhea, and slight weight gain.
Moderate symptoms include excessive weight gain (weight
gain of greater than 2 pounds per day), increased abdominal
girth, vomiting, diarrhea, darker urine and less in amount,
excessive thirst, and skin and/or hair feeling dry (in addition
to mild symptoms). Severe symptoms are fullness/bloating
above the waist, shortness of breath, pleural effusion,
urination significantly darker or has ceased, calf and chest
pains, marked abdominal bloating or distention, and lower
abdominal pains (in addition to mild and moderate
symptoms).
Surgical treatment
Hysteroscopy - A hysteroscopy is an outpatient procedure in
which a narrow fiberoptic telescope inserted into uterus through
the cervix, to look for and sometimes remove adhesions inside
uterus.

Laparoscopy - A laparoscopy is an outpatient surgical
procedure in which a narrow fiberoptic telescope inserted
through an incision near navel to look for and sometimes remove
adhesions in pelvic cavity, remove ovarian cysts or remove or
repair a fluid-filled hydrosalpin or ovarian drilling

Fallopian Tube Sterilization Reversal (reanastomosis) - A
tubal reversal is a surgical procedure performed to reconnect the
two ends of the fallopian tubes in an effort to reverse
sterilization.

Hydrosalpinx removal - A hydrosalpinx is an obstructed
fallopian tube that leads to an accumulation of fluid. Removal of
the affected tube can increase IVF success rates.

Combined infertility

In some cases, both the man and woman may be infertile or
sub-fertile, and the couple's infertility arises from the combination
of these conditions. In other cases, the cause is suspected to be
immunological or genetic; it may be that each partner is
independently fertile but the couple cannot conceive together
without assistance.
Unexplained infertility

up to 20% of infertile couples have unexplained
infertility. In these cases abnormalities are likely to
be present but not detected by current methods.
Possible problems could be that the egg is not
released at the optimum time for fertilization, that it
may not enter the fallopian tube, sperm may not
be able to reach the egg, fertilization may fail to
occur, transport of the zygote may be disturbed, or
implantation fails. It is increasingly recognized that
egg quality is of critical importance and women of
advanced maternal age have eggs of reduced
capacity for normal and successful fertilization.
Fertilization
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