Infertility

Notes
  • This is the failure to conceive after one year of sexual intercourse without contraception.
  • It is described as Primary infertility when a woman has never conceived and Secondary infertility when a woman has conceived previously.
  • Statistics: It affects 8% of women of reproductive age in developing countries and about 11.9% women in Kenya; the WHO - Multicentre study from 1982 to 1985 established the following distribution pattern of causes of infertility: Male Factors - 20%, Female factors - 38%, Causal factors identified in both - 27%, and Not satisfactorily attributed to either - 5%.

##Causes of infertility in women include the following:

  • Factors that affect ovulation including

polycystic ovary syndrome, hyperthyroidism, hypothyroidism and premature ovarian failure (when ovaries stop working before the age of 40)

  • Endocrine disorder in a woman
  • Bilateral occlusion of fallopian tubes as a result of diseases such as pelvic inflammatory disease (PID), scarring from cervical or pelvic surgery, among others.
  • Previous infections with TB, schistosomiasis, filariasis among others.
  • Abnormalities of cervical mucus
  • Submucosal fibroids
  • Endometriosis (especially when endometrium has grown on /in ovaries)
  • Sperm antibodies
  • Drugs such as NSAIDS, spironolactone, anti-cancers and neuroleptics
  • Congenital disorders
  • Age
  • Idiopathic (in about 25% of cases)
  • Being underweight overweight
  • Smoking
  • Stress

##Causes of infertility in men include the following:

  • Blocking of sperm ducts in male due to infections such as STIs
  • Oligospermia (low sperm count)
  • Asthenozoospermia (low sperm motility)
  • Azoospermia (no sperm at all)
  • Teratozoospermia (abnormal sperm morphology)
  • Defects /conditions of testicles such as testicular injury, cancer, infection and failure to descend.
  • Retrograde ejaculation
  • Hypogonadism
  • Drug abuse (such as anabolic steroids)
  • Being underweight or overweight
  • Smoking
  • Stress
Symptoms
  • Failure to conceive after one year of sexual intercourse without contraception
Diagnosis
  • Clinical evaluation of couples
  • Basal body temperature
  • Analysis of semen
  • Hormone analysis
  • Endometrial biopsy
  • Dye laparoscopy
  • Hysterosalpingography (HSG) for tubal patency (dye or saline and air is injected in the cervix and patency of fallopian tube is observed by ultrasound)
Differential
  • Various cancers
  • UTIs
  • Infertility of a partner
Prevention
  • Effective treatment of STI
  • Treatment of underlying diseases such as hypothyroidism
  • Use of condoms when required
  • Avoid drugs and alcohol
  • Regular medical check-up
Management
  • Fertility treatments in women is divided into three categories namely medication treatments, surgical treatments and Assisted Reproductive Technology (ART)

## Medication treatments of infertility

  • Drugs are mainly useful in treatment of problems in ovulation due to hormonal imbalance without any other challenge.
  • Clomiphene

_It is used in the treatment of infertility due to anovulation or oligo-ovulation.

_The following conditions must be met for the drug to be effective as an anti-infertility agent: adequate sperm by the sexual partner, functional hypothalamic-hypophyseal-ovarian systems and adequate endogenous estrogen

_ It is an anti-oestrogen that exerts its effects by competing with estrogen for binding sites at the hypothalamic level. In effect, FSH and LH secretions are increased.

_Dose: 50mg OD x 5/7 starting from the 3rd to 5th day of menstruation or any day if the cycle has ceased.  If ovulation does not occur after the 1st course a second course is given: 100mg OD x 5/7

  • FSH

_ It is mainly used after the failure of clomiphene therapy

_A stepwise gradually increasing dosing scheme can be used. Starting dose of 75 IU  is given for up to 14 days. The dose is then increased by 37.5 IU at weekly intervals until follicular growth and/or serum oestradiol levels indicate an adequate response (max. dose - 300 IU).

_The patient is treated until ultrasonic visualizations and/or serum estradiol determinations indicate pre-ovulatory conditions equivalent to or greater than those of the normal individual followed by hCG, 5000 IU to 10,000 IU.

_If the ovaries are abnormally enlarged on the last day of follitropin therapy, hCG must be withheld during this course of treatment; this will reduce the chances of developing OHSS.  

  • Bromocriptine or Cabergoline

_They are taken orally to treat abnormally high levels of the hormone prolactin, which can hinder ovulation

_The dose of Bromocriptine is 1.25mg-30mg daily in 2-3 divided doses.

##Surgical treatment

_Surgery to repair the tubes or remove blockages in the tubes.

_Surgery to remove patches of endometriosis

_Surgery to remove uterine fibroids, polyps, or scarring, which can affect fertility.

##In vitro fertilization (IVF) Assisted Reproductive Technique (ART)

  • It is suitable for treatment of infertility due to endometriosis, sperm antibodies, tubal dysfunction, failure of intrauterine insemination (IUI) cycles, failure of ovarian stimulation cycles with oral or injectable drugs, age-related decrease of "ovarian reserve, male factor infertility (such as oligospermia), Polycystic Ovary Syndrome (PCO) and idiopathic infertility. It is carried out as follows:
  • Overstimulation of ovary

_Two protocols are used for overstimulation of ovary: Pituitary Down-Regulation Protocol and “Flare-up” Protocol

   Pituitary Down-Regulation Protocol is the most popular protocol and it involves the following steps:

_The process usually starts with the onset of a menstrual period.

_A full cycle of oral contraceptive is started within the 4 days of the menstrual cycle to prime the ovaries for optimal response.

_Seven (7) days before the expected onset of the next menstrual period, a daily SC injection course of Leuprorelin (a gonadotropin-releasing hormone analogue) is started to prevents premature release of the oocytes from the ovaries prior to the oocyte retrieval procedure (and to reduce the level of male hormones to improve the quality of oocytes). Its administration is continued even after menstruation together with FSH (or a combination of FSH/LH) 

_The menstrual period will start.

_Immediately after the menstrual period begins, FSH (or a combination of FSH/LH) SC injection will be administered daily for 10 days to stimulate the production of multiple oocytes in the ovaries. At the same time, Leuprorelin is still administered.

_As FSH (or a combination of FSH/LH) and Leuprorelin administration continues, estradiol and progesterone blood levels are monitored. The ovarian follicles are also monitored using Ultrasound to ascertain whether they have reached the appropriate size

_ FSH (or a combination of FSH/LH) and Leuprorelin are stopped

_A single injection of Human Chorionic Gonadotropin (HCG) is administered SC to triggers the final stages of oocyte maturation

_Oocytes are retrieved 36 hours after the HCG injection

   The “Flare-up” of ovarian overstimulation Protocol involves the following steps

_The process usually starts with the onset of a menstrual period.

_A full cycle of oral contraceptive is started within the 4 days of the menstrual cycle to prime the ovaries for optimal response.

_Seven (7) days after stopping oral contraceptive (or about 3-4 day after the start of the 2nd menstrual cycle), Leuprorelin SC single injection will be administered followed by a course of FSH or sometimes FSH is administered without Leuprorelin for 4-6 days.

_While still administering FSH, monitor the diameter of the follicles and once it reaches 4 mm, administer Clomiphene tablets once daily for three to six days to enhance ovarian stimulation and reduces the likelihood of premature ovulation.

_As FSH (or a combination of FSH/LH) and Clomiphene administration continues, estradiol and progesterone blood levels are monitored. The ovarian follicles are also monitored using Ultrasound to ascertain whether they have reached the appropriate size

_ FSH (or a combination of FSH/LH) and Clomiphene are stopped

_A single injection of Human Chorionic Gonadotropin (HCG) is administered SC to triggers the final stages of oocyte maturation

_Oocytes are retrieved 36 hours after the HCG injection

  • Oocyte retrieval

_This is usually done transvaginally with ultrasound guidance (though it is sometimes done laparoscopically). Under ultrasound guidance, the tip of a thin needle is passed through the top of the vagina into the cul-de-sac. The ovaries are located near the bottom of the cul-de-sac allowing the tip of the aspirating needle to enter the ovarian follicles and aspirate the follicular fluid from them.

_The fluid is examined under a microscope to identify the Oocytes.

  • Fertilization

-The semen sample is collected mainly by masturbation, collected store, washed with tissue culture medium and concentrated for motile sperm, is added to the oocytes at least 6 hrs after retrieval of oocytes

  • Culture of Embryos

_The oocytes and semen are cultured for about 2 to 5 days to allow fertilization.

(If the sperm test a possibility of significant male infertility, Intracytoplasmic Sperm Injection (ICSI) where  a single sperm is inserted into an oocyte)

_A fertilized oocyte (zygote) will microscopically show two pronuclei (one from oocyte and another from sperm). In day 2 embryos divides into 4 cells. On day 3 there are 8 cells, and by the 5th – 7th  after the oocyte retrieval, the embryos should reach the blastocyst stage (≥ 80 cells).

  • Embryo Transfer

_Fertilized embryo (sometimes it can more than one) is transferred to the uterine cavity by placing it into the tip of an embryo transfer catheter then passing it through the cervical canal to within 15 mm of the top of the uterine cavity and releasing it gently.

  • Implantation

_Vaginal progesterone capsules are administered to supplement the ovarian progesterone and estrogen production that make endometrium more receptive to the embryo.

_A serum pregnancy test is carried out 2 wks after the embryo transfer and if positive it is followed by Ultrasound examination 2wks later to ascertain the implantation site and the heartbeat within the embryo.

  • Some embryos are stored in liquid nitrogen frozen for transfer in a subsequent cycle.

##Treatment of men related infertility

  • Aspiration of sperms from testicles or from the epididymis can be used to treat infertility associated with previous vasectomy, congenital absence of vas deferens, and in cases of low sperm concentration and/or quality.

##Artificial insemination (treatment of male infertility)

  • It can either be intracervical or intrauterine insemination.
  • It is preferred by women who desire to give birth to their own child but the male partner is suffering from male infertility.
  • Since the timing of insemination is critical for the success of the process, the following parameters are monitored: ovulation, ultrasound, basal body temperature, color and texture of the vaginal mucus and sometimes the softness of the nose of the cervix

##A surrogate carrier (treatment of infertility when the female of the couple does not produce healthy eggs that can be fertilized)

  • Woman volunteer is inseminated with sperm from the male partner of a couple.

##A gestational carrier (treatment of cases where a woman produces healthy eggs but is unable to carry a pregnancy to term).

  • An embryo from a couple is implanted into a volunteer woman (gestational carrier) who will carry the pregnancy to term.

##Egg donation (treatment of situation where a woman does not produce eggs that can be fertilized)

  • The donated egg is fertilized by sperm from the woman's partner, and the resulting embryo is placed into the woman's uterus.
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