Infertility and its management

1. Dr Liesl Brown
Senior Lecturer
Dept. of Pharmacy
University of Limpopo (Medunsa Campus)
Module 3.4: Endocrine and Reproductive Pharmacy

2.  First successful in-vitro fertilization (IVF) done > 3 decades ago (child =
Louise Joy Brown (DOB: 25 July 1978, weighed: 2.608 kg, UK – became
pregnant naturally herself in 2006)
 Through technology, it is now possible for a woman:
 to give birth to her own grandchild (surrogacy);
 to have a baby after menopause;
 to have twins born years apart (embryo freezing) and
 to have an ovary transplanted from an aborted fetus
Statements:
 ‘… Seemingly, there is no longer a point at which an infertile couple must
abandon hope…’ HOPE
 ‘… It is up to infertile couples to rein in their desperation …’ FORGET IT
 ‘… Should having a biologically related child be an undying quest? …’
MAKE PEACE

3. Infertility:
 The inability to conceive following 12 months of regular coitus without
contraception
 In couples who conceive normally, 50% do so following three tries
whereas about 92% conceive following 12 attempts)
Sterility:
 The etiology of infertility is established and there is no possibility for
conception
Primary infertility: Secondary infertility:
Conception has At least one previous
never taken place conception has been
documented
“Who is affected by infertility?’
Infertility affects men and women of reproductive age worldwide
causing considerable personal suffering and disruption of family life

4.  Globally: 1 in 6 couples (due to sperm dysfunction) (Basin, 2007)
 Sub-Saharan Africa: 30% (male contribution: estimated: 30-50%) (Imade et al.,
2000)
 Prevalence overseas:
e.g.  UK: 2 million infertile couples (1 in 9)
 US: 10-15% of all married couples in the US are infertile
 72.4 million women are infertile; of which 40.5 million is seeking infertility medical
care (estimated on a study done by Boivin et al., 2007)
 Estimates of prevalence: almost 8% - 10% of couples experience some form of
infertility problem during their reproductive lives (not very accurate, vary from
region to region)
  40% of infertility - female factor, 40% - male factor, and the remaining 20% -
mixed male/female factors
 In 10-20% of couples presenting for evaluation, no diagnosis can be made after
standard investigation (unexplained infertility)

5.  The etiology of infertility can be divided
into three major categories:
 female factor
 male factor
 undetermined etiology
Exogenous causes: Endogenous causes:
 STIs e.g. Chlamydia and  For a couple, assessment of the cause
gonorrhea is difficult and time consuming
 Abortion  Both partners must be investigated
 Drug abuse/Marijuana use simultaneously and completely
 Smoking
 Exposure to certain  In developed countries and in higher
chemicals, drugs socio-economic groups, major
/environmental toxins contributors are:
 Cancer, endometriosis, or  ovulatory dysfunction
PCOS  advanced maternal age
 endometriosis
 Stress
 no demonstrable cause
 Poor nutrition
 Intense athletic training

6. • Individualized
• A systematic approach - to evaluate the cause(s) of infertility for a couple
• Research and innovations in the management of infertility have
revolutionized the outlook for the infertile couples
• Now it is possible to offer treatment: 90% - 95% of couples with success
rates varying between 20% - 80% for various modalities of treatment

7. • Preliminary assessment
• Questions: sexual history; durations of cohabitation; sexual
Step 1 problems; menstrual cycle details
• Investigational plan
• Should be as complete as possible and include both partners
Step 2 • Physical examination Laboratory tests - male
- female
• Management strategy
• Pharmacologically induced and normal intervention (sex)
Step 3 • Pharmacologically induced and artificially intervened (ART)
• Non pharmacological options

8. • Investigational plan
Should be as complete as possible and include both partners
Physical examination Laboratory tests
Male Female
• -Ovulation (PCOS)
-Mucus hostility test
-Blood tests
Step 2
• Semen analysis Definitions:
--
-First step of investigation
-Interval of abstinence: 48-72 hrs (A)spermia - complete lack of semen
-collected via masturbation (lab/home)
-instructions for collections NBNBNBNB! (Azoo)spermia - absence of sperm cells in semen
• Normal parameters: (Terato)spermia - sperm with abnormal
• Sperm concentration (10-6 per ml): 15 (12-16) morphology
• Total count: (10-6) per ejaculate): 39 (33-46) (Asthenozoo)spermia - reduced sperm motility
• Ejaculated volume (ml): 1.5 (1.4-1.7)
• Total motile count: (PR + NP, %) : 40 (38-42) (Oligo)spermia - few spermatozoa in semen
• Vitality (live spermatozoa, %): 58 (55-63) (Necrozoo)spermia - total absence of moving
• Sperm morphology (normal forms, %): 4 (3.0-4.0) sperm

9. http://www.flindersivf.com.au/images/malepage/abm_sprm.gif

10. http://www.biol.tsukuba.ac.jp/~macer/BetCD/Bet8sps.JPG

11. Description:
Sperm (at center) incubated at 40C shows hyperactive motility (star-spin pattern) while
other sperm cells show progressive or zero motility. (Fertil. Stertil. 69,118, 1998)
http://www.llu.edu/lluhc/fertility

12. http://syi.hkcampus.net/~syi-kc/sperm.jpg

13. Step 3

14. • Infertile couple
•
• Male Female Other
• Adoption
• Few cases of male factor Surrogacy
• reproductive disorders
• can be remedied
•
Step 3
• Pharmacologically induced Pharmacologically induced
• plus plus
• normal intervention (sex) artificial intervention (ART)
•
•
• Induction of ovulation AI
• Treatment of other conditions GIFT
• Surgery ICSI

15. Non-
Pharmacological
pharmacological
Surgical Other
Pharmacologically
Pharmacologically
induced and
induced and normal
artificially
intervention (sex) Adoption Surrogacy
intervened (ART)

16. (a) Pharmacological induced and normal intervention (sex)
Includes drug treatment of: anovulation; endometriosis and the
treatment of infections e.g. pelvic infections, such as Chlamydia,
gonorrhea, post-abortal and postpartum infections, PID associated with
IUDs
plus
“normal” intercourse
(b) Pharmacologically induced and artificial intervention (ART)
Includes drug treatment of the female
plus
artificial reproductive techniques

17. • The rationale is to drive more than one oocyte to ovulate with each cycle in
order to increase the odds of a pregnancy
• Approximately 10-15% of infertile females are anovulatory
• Causes include:
• extremes of weight
• polycystic ovary syndrome (PCOS)
• emotional stress
• drugs
• systemic illness

18.  A number of medications have been used to help initiate ovulation
including:
 Clomiphene citrate (CC)
 CC + Dexamethasone
 CC + Bromocriptine
 Levothyroxine sodium (Eltroxin)
 Metformin
 Human menopausal gonadotrophins (hMG)
 Human chorionic gonadotrophin (hCG)
 Bromocriptine
 Glucocorticoids
Today if lack of ovulation is the only cause operating in a particular
couple, the chances of conception with treatment equals that of
normal fertile population

19. Clomiphene Citrate (Clomifene citrate) (CC) [SA Essential drug]
 Non-steroidal agent with oestrogenic and anti-oestrogenic properties
 Induces the release of FSH and LH which leads to the maturation of the
ovarian follicle
 May be used with human chorionic gonadotrophin (hCG)
 Indications:
 Management of anovulatory/oligo-ovulatory infertility in women with
an intact hypothalamic-pituitary-ovarian axis
May result in multiple pregnancy, therefore ovarian response should be
monitored via ultrasound and/or endocrine assays

20.  Pharmacokinetics  Contraindications
• Enterohepatic recirculation • Liver disease/history of
hepatic dysfunction
• t0.5 =5-7 days
• Ovarian cysts
• Metabolized in liver
• Undiagnosed abnormal
• Eliminated slowly in faeces
uterine bleeding
via bile
Side effects
Common: Rare:
• Reversible ovarian enlargement Reversible hair loss
• Cyst formation (withdraw Rx) Hepatotoxicity
• Vasomotor flushes
Uncommon: Uncommon (CNS effects):
• Abdominal distension Dizziness
• Nausea and vomiting Nervousness
• Breast discomfort Depression
• Intra-uterine bleeding Fatigue
• Headache Insomnia
• Skin rashes Visual disturbances (blurring vision
• Weight gain diplopia and photophobia
•

21.  Dosing regimen:
 50 mg daily for 5 days starting on day 3-5 of a spontaneous or
induced withdrawal bleed
 If ovulation has occurred, but not conception, use 50 mg again
 Should ovulation failed: 100 mg (single dose) for 5 days
 However, maximum pregnancies are achieved at 50-100 mg dose
 Of these, 5% pregnancies may be multiple almost entirely twins.
There have been some reports of high order multiple pregnancies
 Success rate:
 Many patients responds on first course
 Inducing ovulation in over 90% of cases
 Pregnancy rates approach only 65%
 80% of patients treated with CC get pregnant within 3 cycles of
therapy
 In properly selected cases, 80% women can be expected to
ovulate and approximately 40% become pregnant

22.  Disadvantages:
Advantages: oMultiple pregnancies (5%
o Relatively inexpensive pregnancies may be twins),
o Taken by orally high order multiple
o Few side effects (except a pregnancies
multiple gestation rate of 7% in
anovulatory women and the rare
possibility of inducing
hyperstimulation syndrome)
o The administration of CC early in
the cycle favors multiple
follicular recruitment

23.  Special prescribers points
 Underlying causes of infertility should be investigated (semen analysis, 1st)
 Failure to respond to 3 courses of clomiphene – go for more
comprehensive investigations
 Risk : benefit – assessed in patients with endometriosis, fibroid tumour,
PCOS
 Liver fn – tested prior to therapy initiation
 Risk of multiple pregnancies lowered by monitoring the ovarian response
(ultrasonographically)
 Warm patients: lightheadedness, visual disturbances, precautions when
driving or when performing tasks requiring physical skill

24. (a) Clomiphene Citrate (CC) + Dexamethasone (DEX)
 Patients with hirsutism and high circulating androgen concentrations
are more resistant to CC
(b) Bromocriptine (BRC)
 Excess prolactin inhibits normal hypothalamic pulsative GnRH release
 Anovulatory women with hyperprolactinaemia (first treated with
bromocriptine , before considering ovulation induction drugs)
(c) CC + BRC
 Elevated prolactin levels interfere with the normal function of the
menstrual cycle by suppressing the pulsatile secretion of GnRH. This is
manifested clinically by ovulatory dysfunction
 BRC is a D-antagonist which directly inhibits pituitary secretion of
prolactin. It is a highly successful treatment of hyperprolactinaemic
anovulation
 Results are controversial and extended empirical therapy should be
avoided

25. (d) Levothyroxine sodium (Eltroxin)
• Hypothyroidism, even if subclinical, should be treated and
monitored to achieve euthyroid state
• Empiric use of thyroid extract or Eltroxin is of no use
(e) Metformin
 It acts by lowering insulin resistance and improved
peripheral utilization of glucose
 In obese, hirsute women, metformin + diet control = may
significantly reduce weight + improve results of ovulation
induction

26. Used to help induce ovulation
 HMG contain both LH and FSH for ovulation induction
 HMG are found in the urine of postmenopausal women
Indications:
 Clomiphene failures
 Induction of ovulation in women with PCOS and endometriosis
 Women with a pituitary gland that does not produce FSH or LH
 Controlled ovarian hyper stimulation for ART
Dosing regimen:
 IM
 Usually given 2-3 days after menstruation begins, HMG are
administered daily for 7 to 12 days
 Typical dosage is between 75 and 600 IU/day

27. Side Effects :
 Hyperovarian stimulation
 Mood swings
Multiple pregnancies by a significant amount (40% of all pregnancies that occur while
using this medication are twins or higher order multiples)
Disadvantages:
 Expensive
 Given daily IM and involves much more risk
 Time consuming and have potential serious side effects
 Over dosage may produce a potentially life-threatening ovarian
hyperstimulation syndrome
Success rate:
 The multiple gestation rate is about 15-35%
 A 90% anovulation and 50 - 70% pregnancy rate can be expected
 Between 75% and 85% of patients begin to ovulate after using this medication
 Pregnancy rates tend to be around 60%, although half of these pregnancies will
not be carried to term

28.  hCG is a peptide hormone that is produced in a pregnant woman's
placenta (exclusively by trophoblast)
 It helps to maintain the corpus luteum, which produces progesterone and
oestrogen in order to maintain the first trimester of pregnancy
 hCG is taken from the urine of pregnant women and used to induce
ovulation in some women
 Mechanism of action:
Increase the number of eggs that are released from the follicles each month
It imitates luteinizing hormone (LH), causing your follicles to rupture and
release eggs (often causes ovaries to release more eggs than normal,
thereby increasing the chances of becoming pregnant)
Indications:
anovulation
PCOS (polycystic ovarian syndrome)
irregular periods

29. Directions:
•IM/SC
•Dosages 5,000 to 10,000 units (given a few days before ovulation occurs)
•Dr will monitor follicle and endometrial development through ultrasound
When the follicle size is greater than 18 mm along with simultaneous thickening of endometrium to
more than 8 mm
Injection of hCG to stimulate ovulation (36-48 hours for hCG to begin to work)
(hCG also supports the corpus luteum when given in doses 1500-2000 IU IM on
day 3, 6, 9 post ovulation)
 You and your partner have timed intercourse/IUI

30. Success rate:
hCG is very successful at inducing ovulation (>90% of anovulatory
women begin to ovulate)
Pregnancy rates are around 15% per cycle
Pregnancy rates increase with the use of IUI
hCG can increase your risk of multiple births
Side Effects:
headache
water retention
fatigue
sore breasts
abdominal discomfort
Irritability

31. Glucocorticoids
Acts by suppressing ACTH and therefore adrenal androgen
production
Advantages:
 Occasionally helpful in facilitating ovulation because
circulating androgens cause ovarian follicular atresia
Indications:
 Primarily in PCOS with a component of elevated adrenal
androgen secretion
 In women with congenital adrenal hyperplasia

32. Pharmacological management of endometriosis
 Endometriosis is the ectopic growth of endometrium
 Found in  5-10% of the general population
 Noted in 30-40% of women presenting to infertility clinics
Pharmacological management for the treatment of PID infections
 Pelvic infections e.g. Chlamydia, gonorrhea, post-abortal and
postpartum infections, PID associated with IUD lead to permanent
structural and functional damage to the fallopian tubes
 Medical treatment can only do the microbial clearance
 Any structural or functional damage is more likely to be permanent
Surgical management

33. Definition: ART refers to those procedures where gametes (sperm and oocyte)
handling is done in-vitro (outside the body)
Ifinadequate gametogenesis is the cause, couples are offered therapeutic donor
insemination, donor oocytes or both
Artificial insemination (AI):
AI is timed to coincide with ovulation, sperm from the
husband or a donor is directed into the vagina, the cervix, near the cervix, or in the
uterus (SR: 30-40% per cycle with cumulative pregnancy rate of 70-80% over 3 cycles)
In vitro fertilization (IVF ): Egg and sperm (of husband and wife or of donors) are
collected and joined in a test tube where fertilization occurs
Gamete Intra-Fallopian Transfer (GIFT ): Eggs of a donor and sperm from
husband/donor is placed in the infertile wife’s fallopian tube (SR: 25-30%)
Intra Cytoplasmic Sperm Injection (ICSI): Sperm are aspirated directly from the
epididymus or testicles. After egg retrieval, a single sperm is injected into in an oocyte
with the help of micromanipulator instead of leaving the oocytes and sperms together
in a dish for fertilization (SR: comparative to IVF)

34. http://www.fertilityich.com/images/imgiui.jpg

35. Surrogacy
Definition:
A woman who is AI and carries to term a baby who will be raised by his/her
genetic father and his partner
 The surrogate may be implanted with the husband's sperm and/or the
wife's egg
 Surrogacy gains in popularity
 Single men also seek surrogate mothers for their children
Adoption
 Childless singles and couples may want to consider adoption, especially the
adoption of children who are harder to place e.g.
 with special needs
 sibling groups
 older children
-Locally / Internationally

36.  Limited due to the nature of the problem
 Counseling the patient on correct drug use, adverse effects expected ect.
-The need for a counseling service
-The concept of ‘infertility strain’
-Implications support and therapeutic counseling
-The relationship between counselor and doctor
 Being a pillar of support for the infertile couple
 Source of information (e.g. basics of infertility, telephone no. (social
workers, infertility specialists, counselors etc.)
 Referral to infertility specialists
 Other ???

37.  Infertility is increasing
 Its impact is underestimated & not understood by
the main frame of society
 Couples suffering from infertility needs help
(pharmacologically and psychologically)
 There is hope for some with AI techniques
 Infertility comes with choices

38. Credit: © Gary Martin/Visuals Unlimited 350631
Ovulation (series 2 of 2.) SEM X1500.

39. http://www.sirinet.net/~jgjohnso/eggandsperm3.jpg

40. This spiral represents the 23 stages occurring in the first trimester of pregnancy and
every two weeks of the second and third trimesters. Use the spiral to navigate through
the 40 weeks of pregnancy and preview the unique changes in each stage of human
development. http://www.visembryo.com/baby/

41. Description
Ultrasound scan of a fetus at 19.5 weeks gestation
http://www.rba-online.com/