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					                        Infertility
• Definitions:

• Infertility is defined as the inability of a couple to
  conceive after 1 year of frequent unprotected
  intercourse without contraception

• Subfertilty : diminished capacity to conceive

• Fecundability is defined as the probability of achieving a
  pregnancy within one menstrual cycle, (in normal couples
  the chance of conception after 1 month is approximately 25%).
              types
               Types




                       Secondary
Primary
                       difficulty in
where the
                       conceiving after
couple have
                       already having
never
                       conceived and
achieved a
                       carried a normal
pregnancy
                       pregnancy
• Infertility: attributing causes in:

• Female           58%

• Male             25

• Unknown          17%

• modifiable risk factors smoking, alcohol,
  caffeine, and obesity
• Female subfertility can be classified as:

•   (1) ovulatory defects

•   (2) pelvic disorders

•   (3) male factors.

• These factors account for 80–85% of couples diagnosed
  with infertility.
• about 15% of couples have more than one cause of
  subfertility.
• In approximately 20% of couples, the cause remains
  unknown and is classified as unexplained infertility.
• Fertility and Age
• Increasing age is an independent risk factor for decreased fertility and is
  attributed mostly to the ovary. By the age of 35 a woman has half the chance of
  becoming pregnant than a 25-year-old.

• Spontaneous abortion rate increases with advancing age largely attributed to
  abnormalities in the aging oocyte: older follicles have an increased rate of
  meiotic dysfunction, resulting in higher rates of chromosomal abnormalities

• Follicular loss is a progressive process that will deplete the germ cell pool by
  menopause. This loss is independent of hormonal therapy, such as birth control
  pills, and accelerates the last decade before menopause.
• 3

• Recipients of donated oocytes will have pregnancy and live birth rates close to
  those of the age group of the donor.


•   The age of the male does not impact on the ability of the sperm to fertilize anoocyte.5
               Infertility : case Hx

• A 28-year-old woman has been unable to
  conceive a baby for 7years.
• She has irregular menstrual cycles (22 to 36
  days) and no physical complaints.
• Her husband has a normal sperm count, and
  the sperm have normal motility and
  morphology.
• She seeks investigation of her infertility.
• General physical examination is entirely
  normal.
• The external genitalia have a normal
  female pattern.
• A normal-sized uterus and ovaries are
  palpated.
• Confirmed by ultra sound examination of
  the pelvis.
         Infertility : line of approach to the pt’s problem

• Thinking in physiologic sequence, what are the possible
  causes of a woman’s failure to conceive?

• What evidence could you seek to investigate each
  possible defect in the sequence that you have
  considered?

• What treatment could you design to correct each
  physiologic defect?
Possible physiological implications in the given patient:

a. Failure of capacitation in pt’s vaginal tract

b. Rejection of husband’s sperm by pt’s ovum during fertilization
    (antisperm antibodies)

c. Non- recruitment & development of a dominant follicle

d. Failure of ovulation of dominant follicle.
   Failure of formation      or            faiure normal functioning of CL
                                                       
Inadequate nourishment of fertilized          inadequate preparation of an
             ovum                             implantation site

e. Inability of a diseased ipsilateral F tube to pick up an ovulated egg
                               OR
     -Diseased tube does not allow ascent of sperm or descent of fertilized ovum
 f. Local uterine abnormalities no secure implantation (undetected
                                                            abortions
                           Infertility
• Common Causes of           • ovulatory dysfunction and abnormalities
                               of the uterus or outflow tract,
  Infertility                • amenorrhea or as irregular or short
                               menstrual cycles.

                             • laboratory tests to determine whether
• Pelvic pathology             the abnormality is
                             • (1) hypothalamic or pituitary [low FSH),
  (tubal disease and           LH, and estradiol with or without an
  endometriosis)               increase in prolactin];

                             • (2) polycystic ovarian syndrome (PCOS;
                               irregular cycles and hyperandrogenism
• Disorders of ovulation       in the absence of other causes of
                               androgen excess). Polycyst ovaries not a
                               Dxtic feature

• Idiopathic infertility     • (3) ovarian (low estradiol with increased
                               FSH)

• Male related disorders     • (4) uterine or outflow tract abnormality.
• Fertility tests for women:


•   1. Patency and health of reproductive tract:
          Cx, uterus, fallopian tubes


    2. Ovulation: occurs or not

    3. Response of endometrium to hormones



    4. Any Infections /tumours of the reproductive tract
               Menstrual cycle:   Recall


  FSH
   LH



  Estrogen

Progesterone
• All anovulatory patients should have
  determination of PRL and TSH levels—and, if
  necessary, androgen levels—to identify the cause
  of the ovulatory disturbance.
• Post ovulation
• Luteal-phase defect: inadequate quantity or duration of
  progesterone secretion by the corpus luteum. Progesterone
  deficiency may desynchronize ovulation (egg) and implantation
  (endometrium).

• Typically, the diagnosis is established by luteal phase
  endometrial dating; if the histologic development of the
  endometrium lags more than 2 days beyond the day of the cycle,
  it is diagnostic of a luteal phase defect. However, up to 30% of
  women with normal cycles meet this criterion.

• Midluteal progesterone level if less than 10 ng/mL luteal phase
  defect. not reliable because progesterone is intermittently
  secreted, and the serum progesterone level can change from 1
  hour to the next in the same individual
Fertilization & implantation
• Pelvic inflammatory disease and infertility
• Uterine tube damage and adhesion formation
  (chronic salpingitis) : TB, STD

• Endometriosis as a primary cause of subfertility.
• Endometriosis: endometrial glands and stroma
  outside of the uterus.
• Only manifestation may be infertility,
• or symptoms may progress to include severe pelvic
  pain, dysmenorrhea, and dyspareunia.
• The diagnosis is suspected on surgical exploration,
  confirmed with biopsy of the peritoneal lesions.
• Incidence: about 3–10% of reproductive age
  women;
• may be responsible for up to 25–35% of the
  female factors responsible for subfertility
• Pathophysiology of endometriosis



• Immune system should normally dispose of the tissue

• Altered immunity may result in implantation of this
  endometrial tissue outside the uterus in those women who
  subsequently develop endometriosis.
What evidence could you seek to investigate each possible defect in the
sequence that you have considered?



   Failure of capacitation   -Sperms recovered after intercourse examined for
                             motility
                             -ability to penetrate determined in vitro (interaction
                             with a test ovum)


   Rejection of husband’s    -Presence of Ab to sperm sought in patient’s ova or
   sperm                     sera
   Inability to develop a    -Reflected by absence of accelerated rise in
   dominant follicle           Estrogen during late follicular phase
                             - Inadequate FSH OR LH due to hypoth OR ant.
                                Pit. Disease
   Lack of normal            -No midcycle surge in plasma or urine LH or FSH
   ovulatory signal          -Dominant follicles degenerate (ultrasound)
Blockage of fallopian tubes           Demonstrated by injection of x-ray dye
                                      in uterus

Failure of CL function                -No rise in plasma P during luteal phase
                                      --Absence of secretory endom
                                      -cervical mucous pattern



No implantationundetected abortion   -transient rise in plasma HCG late in
                                      cycle
   Infertility: Physiological principles of management


Induction of ovulation by:
1. pulsatile GnRH.
2. Clomiphene citrate
3. Gonadotropins

Clomiphene citrate : nonsteroidal estrogen antagonist that
   increases FSH and LH levels by blocking estrogen negative
   feedback at the hypothalamus.
   induces ovulation in 70 to 80% of women with PCOS
Clomiphene citrate is less successful in patients with
   hypogonadotropic hypogonadism.
                   Hysterosalpingogram

                   Hysteroscopy and falloposcopy
Investigation of
Fallopian tubes      post-coital test (Sims-Huhner's Test).
    & uterus
                       (mid-cycle mucus).

              laparoscopy and dye test.
• Hysterosalpingogram (HSG):
  – demonstrate a blockage in the tubes;
  – demonstrate an abnormality within the uterus.
  – has to be performed in the first half of the cycle after
    menstruation has stopped and before ovulation, to avoid
    x-ray exposure to a fertilized egg.


• Other test:
  – Hysteroscopy and falloposcopy


• Post-coital test (Sims-Huhner's Test):
  – Test of cervical mucus after 2-6hrs of intercourse to look
    for present motile sperm
                                           assisted
medicine
                     RX                  reproductive
                                          technology




           surgery        Artificial
                          insemination
                              Medical treatment
•    Clomiphene citrate (Clomid):
    causes ovulation by acting on the pituitary gland. It is often used in women who have
     problems with ovulation.

•    progesterone:
    IF infertility due to inadequate luteal phase.

•   human Menopause Gonadotropin (hMG): extracted from urine of post menopausal women
    used for women who don't ovulate due to problems with the pituitary gland, acts directly on
    the ovaries to stimulate ovulation.

•    Follicle-stimulating hormone (FSH):
    causes the ovaries to begin the process of ovulation.

•   Gonadotropin-releasing hormone (GnRH) analog:
    used for whom don't ovulate regularly or ovulate before the egg is ready.

•   Bromocriptine: for ovulation problems due to high levels of prolactin.
• Gonadotropins are highly effective for ovulation induction in
  women with hypogonadotropic hypogonadism and PCOS

•   are used to induce multiple follicular recruitment in
    unexplained infertility and in older reproductive-aged women.

• FSH is the key component, the addition of some LH (or human
  chorionic gonadotropin) may improve results, particularly in
  hypogonadotropic patients.

•    Disadvantages include a significant risk of multiple gestation
    and the risk of ovarian hyperstimulation,

• Gonadotropins include urinary preparations of LH and FSH,
  highly purified FSH
        Surgical treatment


• For tubal obstruction microsurgical,
  tuboplasty or neosalpingostomy.

• Endometriosis sub-mucosal
  myotomy,.laproscopy.
•   Assisted reproductive techniques are
    usually used after other techniques to
    treat infertility have failed.

•   In-vitro fertilization
•   GIFT (gamete intrafallopian transfer)
•   ZIFT (zygote intrafallopian tube transfer)
                  Assisted Fertilization techniques
•   In-vitro fertilization
•   The use of a drug to induce the simultaneous release of many
    eggs which are retrieved surgically.
•   several semen samples are obtained from the male partner, and
    a sperm concentrate is prepared.
•   The ova and sperm are then combined in a laboratory, where
    several of the ova may be fertilized.
•    Cell division is allowed to take place up to the embryo stage.
•   During this, the female may be given drugs to prepare her
    uterus
•   Three or four of the embryos are transferred to the female's
    uterus.
•   Success rates of IVF are still low: between 10-20%.
•    Chances of multiple pregnancies after this are high
•   GIFT (gamete intrafallopian transfer)
•   retrieval of both multiple ova and semen
•    the mechanical placement of both within the female
    partner's fallopian tubes

•   ZIFT (zygote intrafallopian tube transfer)
•   retrieval of ova and semen
•   fertilization and growth in the laboratory up to the
    zygote stage
•   zygotes are placed in the fallopian tubes.
•   Both GIFT and ZIFT seem to have higher success
    rates than IVF.
•   Anovulation

•   The most common cause of anovulation in North America is polycystic ovarian
    syndrome (PCOS).

•   PCOS is a metabolic disorder with a primary reproductive manifestation..
•   Most women with PCOS have insulin resistance that is independent of weight.8.

•   There usually is a strong family history of diabetes or abnormal glucose tolerance.
    PCOS patients that achieve pregnancy often have gestational diabetes.


•   Obesity is an independent disorder with associated endocrine changes that influence
    the phenotypic expression of PCOS patients.

•   There is a genetic predisposition to insulin resistance because of a post-receptor
    abnormality such as with a glucose transporter rather than a receptor defect.
•   Insulin can directly influence enzymes that are involved in androgen steroidogenesis
    as well as decreasing sex hormone binding globulin.
Male factors in Infertility
             Male reproductive Physiology: semen

    Normal semen

•   volume 2-6 ml
•   Contents: sperms; secretions from accessory glands; mucus
•   sperm count > 100 million (< 20 million: infertile)
•   pH alkaline (around 7.5)

• Viability of sperms:
• In male tract : many weeks
• about 48-72 hours in female tract
• for years at < -100 0C
•
           Male reproductive Physiology: male infertility
• 1. Diseases of testes: Mumps which may
  damage seminiferous tubules

• 2. Prolonged exposure to heat : normal
  body temp. gradient to scrotum: 20 C

• 3. Cryptorchidism: testes degenerate if in
  abdomen

• 4. Sperm count < 20 million/μlitre
                                                            normal
• 5. Abnormal sperm morphology

• 6. role of membrane based Angio II CE
  in sperms – seen in mice. Humans ??
•   Male factors in Infertility

•   i. Environmental toxins, drugs such as cimetidine, heavy cigarette, marijuana and alcohol
    use can be associated with decreased sperm parameters and reduced fertility.

•   ii. Chemotherapy and radiotherapy are associated with severely depressed sperm counts
    that are sometimes irreversible.
•    Patients may cryo-preserve sperm before initiating treatment.
•     Excellent success rates have been reported with the use of this sperm.

•   iii. Increased scrotal temperature as a result of a febrile illness can cause a temporary
    alteration of semen parameters that is only identified 2 to 3 months after the episode. This
    is the time required for a germ cell to develop into a mature spermatozoon.


•   Radiant heat, such as experienced by welders or foundry workers, may also affect semen
    quality.
•   Long hours on computers

    conditions that result in a minor increase in scrotal temperature only, such as tight
    underwear, have not been shown to alter sperm function.7
                CatSper: enzyme which
               promotes flagellate activity




                                              Acrosomal enzymes:
Germinal AIICE in                               hyaluronidase;
membrane
?fertility function
                                              Proteolytic enzymes

				
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posted:8/27/2011
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