Presentation given at the weekly departmental seminar of the LAUTECH teaching hospital, Ogbomoso. Nigeria

1. .

2. N
 Anovulation is the failure to release an oocyte from a mature graafian
follicle during a menstrual cycle (in a post-menarcheal, premenopausal
woman)
 Usually manifests itself as irregularity of menstrual periods, that is,
unpredictable variability of intervals, duration, or bleeding
 Most of these women have oligomenorrhea, arbitrarily defined as
menstruation that occurs at intervals of 35 days to six months.
 Infertility is the inability of a couple to achieve pregnancy after twelve
months of adequate unprotected sexual intercourse.
 14% of couples according to this criteria (9% primary, 5% secondary)
 Anovulatory infertility affects a large proportion of reproductive-aged
women
 Commonest cause of infertility in developed countries

3. N
 Up to 40%, representing 5 million couples in the United States alone
(Barbieri 1999; Hull 1987)
 Studies from Nigeria 20% of cases, more common causes of infertility
being tubal factors 34.4% [Giwa-osagie OF et al Int J. of fertility 1984
29(2)]
 Increasing concern in terms of maintaining a sufficiently large and
relatively youthful workforce
 Heightened stress on the woman and couple, with significant financial
strain on the family and society
 The costs per pregnancy of three different strategies were compared,
with a threshold for cost-effectiveness of €10 000 [Marinus J.C. et al Ox. J
of humRep 2005 20(10)]
 A structured approach, starting with low-cost interventions and
advancing to high resource interventions, is warranted for treatment of
anovulatory infertility

4. OVULATION

5. R
 Laparoscopic ovarian drilling (LOD) is associated with an increased risk of
multiple Pregnancy
 Premature ovarian failure is irreversible
 More triplets, quadruplets and quintuplets are born as a result of in vitro
fertilisation/intracytoplasmic sperm injection (IVF/ICSI) than ovulation
induction
 50% of all women achieving pregnancy do so on the 50 mg dose of
clomid
 OHSS does not occur in the absence of luteinisation by human chorionic
gonadotrophin or luteinizing hormone (LH).
 OHSS is seen more often in women who are obese.
 Evidence suggests that recombinant FSH results in better pregnancy rates
than purified FSH.

6. ANOVULATION
Group Description Features Examples
I
5-10%
Hypogonadotropic
hypogonadal
anovulation
(Hypothalamic-
Pituitary failure)
These women have low or low-normal serum follicle-
stimulating hormone (FSH) concentrations and low serum
estradiol concentrations due to decreased hypothalamic
secretion of gonadotropin-releasing hormone (GnRH) or
pituitary unresponsiveness to GnRH
Kallmann's synd.,
Amenorrhea ass. with wt.
loss, stress, idiopathic
Hypogonadotropic
hypogonadism, Sheehan syn.
II
70-
85%
Normogonadotropic
normoestrogenic
anovulation
(Hypothalamic-
Pituitary
dysfunction)
These women may secrete normal amounts of
gonadotropins and estrogens. However, FSH secretion
during the follicular phase of the cycle is subnormal. This
group includes women with polycystic ovary syndrome
(PCOS). Some ovulate occasionally, especially those with
oligomenorrhea
Polycystic Ovarian Syndrome
III
10-
30%
Hypergonadotropic
hypoestrogenic
anovulation (Ovarian
failure)
The primary causes are premature ovarian failure (absence
of ovarian follicles due to early menopause) and ovarian
resistance (follicular form). High gonadotropins, low
oestrogen.
Turner synd.,
premature/autoimmune
ovarian failure, chemo/radio
Rx-induced ovarian damage.
IV Hyperprolactinemic
anovulation
A separate category; Hyperprolactinemia inhibits
gonadotropin and therefore estrogen secretion. Normal or
decreased gonadotropins
Prolactin-producing
adenoma, primary
hypothyroidism, CRF, drugs.

7. DYSFUNCTION
1) INTRINSIC OVARIAN FAILURE (WHO group III)
genetic, autoimmune, following chemotherapy or radiotherapy
2) SECONDARY OVARIAN DYSFUNCTION
a) Disorders of gonadotropin regulation
I) SPECIFIC: Hyperprolactinaemia (WHO group IV)
Kallmann’s syndrome (WHO group I)
II) FUNCTIONAL: Weight loss, exercise, drugs, idiopathic (WHO group I)
b) Gonadotropin deficiency (WHO group I): Pituitary tumour, pituitary necrosis/
, thrombosis
c) Disorders of gonadotropin action (WHO group II): Polycystic ovary syndrome

8. MANAGEMENT
 Oligoovulation/Anovulation unrelated to ovarian failure can usually be
treated successfully with ovulation induction.
 These women achieve fecundability equivalent to that of normal couples
 15 to 25% probability of achieving a pregnancy in one menstrual cycle
(Collins JA et al. N Engl J Med 1983; 309:1201)
 The method of ovulation induction selected should be based upon:
- underlying cause of anovulation
- efficacy
- costs
- risks
- potential complications associated with each method.
- drug availability/accessibility of choice of tx to patient

9. MANAGEMENT
Options include:
 Weight modulation
 Clomiphene citrate or other selective estrogen receptor modulators
(SERMs)
 Metformin or other insulin-sensitizing agents
 Aromatase inhibitors
 Gonadotropin therapy
 Laparoscopic ovarian drilling
 Bromocriptine or other dopamine agonist (only in cases of
hyperprolactinemia and anovulation)
 Assisted reproductive technology

10. MANAGEMENT
 Most of these approaches are effective for WHO class 2 patients.
 WHO class 1 patients respond best to therapy involving lifestyle
modification or gonadotropins.
 Some WHO class 3 patients respond to gonadotropin therapy and in vitro
fertilization (IVF), but those who fail require oocyte donation
 Adequate history and physical examination are essential.
 Adequate patient counseling/patient information leaflets
 Correct any underlying disorder
 Optimize health before starting therapy
 Exclude other causes of infertility (semen analysis, tests of tubal patency,
TFT etc. as indicated)
 Induce regular unifollicular ovulation

12. NS
 Documentation of ovulation very important
 Direct assays of gonadotropins or steroid hormones in the serum, urine,
or saliva
 Evaluation of peripheral changes preceding, coinciding with, or
succeeding the ovulatory process
 Hormone Assays:
- Serum/urinary LH (0.5–14.5 IU/L)
- FSH <10 IU/L optimal reproductive potential (10-15IU/L borderline)
- Estrogen Assays (E2) >75-80pg/ml ass. with reduced ovarian reserve
 Have the potential both of predicting ovulation and identifying the limits
of the fertile period.
 Progesterone Assays: Day 8 and Day 21 (of a 28 day cycle) A rise of value
from <1 ng/mL to >5 ng/mL would be consistent with ovulation.

13. NS
 Ultrasonography :
- Size; as ovaries depleted of eggs tend to be smaller
- Follicular tracking, Ovulation is deemed to have occurred if the follicle
reached a mean diameter of 18–25 mm and subsequently changed in
size, shape, or sonographic density.
 The changes in ultrasound image of the follicle that rupture are:
(1) disappearance or sudden decrease in size
(2) increased echogenicity
(3) irregularity of follicular wall
(4) appearance of free fluid in the cul de sac of Douglas.
 Disappearance or sudden decrease in follicle size has been found to be
the most frequent sign of ovulation. Sensitivity and specificity of
ultrasonography to document ovulation is 84% and 89%, respectively,
and accuracy is about 85%

14. NS
 Anti-Mullerian Hormone (AMH) testing:
- correlates with the number of antral follicles in the ovaries
- levels do not vary with the menstrual cycle and can be measured
independently of the day of the menstrual cycle and decrease with age.
- Healthy women, below 38 years old, with normal follicular status at day
3 of the menstrual cycle, have AMH levels of 2.0 - 6.8 ng/ml (14.28 -
48.55 pmol/L).
- High levels are found in patients with PCOD, which compromises female
fertility
 Antral follicle count/Ovarian reserve:
- Counted by vaginal USS
- along with female age, the best tool that we currently have for
estimating ovarian reserve, the expected response to ovarian stimulating
drugs, and the chance for successful pregnancy with in vitro fertilization.

15. NS

16. NS

17. NS

18. NS
Advanced Fertility Center of Chicago

19. NS
Other tests:
 Basal serum Inhibin B (< 400 pg/ml) ass. with poor ovarian reserve
 Clomiphene citrate challenge test
 Exogenous FSH ovarian reserve test
 Gonadotrophin releasing hormone agonist stimulation test
 Ovarian volume
 Ovarian vascularity
 Ovarian biopsy
 Endometrial biopsy (in the secretory phase)
 Endometrial plate measurement

20. TREATMENT OPTIONS FOR WHO GROUP I (HYPOGONADOTROPIC
HYPOGONADISM)
 Supervised programs for weight optimization.
 Pulsatile administration of gonadotrophin-releasing hormone (GnRH)
agonists.
 Gonadotrophin (with LH activity) regimens.
 GnRH, administered subcutaneously (15–20 micrograms usually every 90
minutes) or intravenously (5 micrograms every 90minutes) in a pulsatile
manner through a pump
 Gonadotrophins regimens are discussed later under treatment options
for who group II
 For WHO group I ovulatory disorders, gonadotrophins with luteinizing
activity are better at inducing ovulation than pure FSH preparations.
 Clomiphene is ineffective in the absence of an intact hypothalamic–
pituitary axis and therefore it is not appropriate as a treatment in this
group of anovulatory women

21. TREATMENT OPTIONS FOR WHO GROUP II NORMOGONADOTROPHIC
ANOVULATION
 Heterogeneous group of patients who can present either with regular
cycles, oligomenorrhoea, or even amenorrhoea.
 Most of these patients are likely to have PCOS (~80%)
 Other causes include congenital adrenal hyperplasia, adrenal tumours,
and androgen-producing ovarian tumors
 The patient may have clinical symptoms or signs of hyperandrogenism
such as hirsutism, which should require more detailed investigations such
as measurement of dehydro-epianderosterone sulphate and 17-OH
progesterone
 Specific causes, such as adrenal or ovarian tumours, should be treated by
removing the cause. Congenital adrenal hyperplasia benefits from
corticosteroid therapy.

22. SYNDROME (PCOS)
 PCOS is a heterogeneous collection of signs and symptoms that, gathered
together, form a spectrum of a disorder with a mild presentation in
some, whilst in others it causes severe disturbance of reproductive,
endocrine and metabolic function:
- Oligo- and/or anovulation
- Hyperandrogenism (clinical and/or biochemical);
- Polycystic ovaries, with the exclusion of other etiologies.
 Treatment:
 Effective use of ovulation induction agents.
 requires understanding of their mechanism of action, proper indications,
different regimens, monitoring methods, and potential complications.

23. SYNDROME (PCOS)
Regimens Commonly Used Includes:
• Clomiphene, tamoxifen
• Clomiphene, tamoxifen with intrauterine insemination
• Metformin in combination with clomiphene
• Gonadotrophins
• Gonadotrophins with GnRH analogues
• Ovarian drilling – lod, laser

24. SYNDROME (PCOS)
Points To Consider Before Ovulation Induction:
i. Selection of appropriate treatment
ii. Total motile sperm count of at least five million/ejaculate.
iii. Advice on weight control (gain/loss to achieve a BMI of <30kg/m2 or
>20kg/m2)
iv. Adequate counselling of women regarding the risks of treatment
v. Ovulation induction should only be started if adequate monitoring
facilities (ultrasound and laboratory) are available, together with
protocols with clear guidelines for reducing risks, which would include
cancellation of treatment cycles.

25. SYNDROME (PCOS)
MEDICAL INDUCTION OF OVULATION
 ANTI-ESTROGENS:
1. Clomiphene Citrate (CC)
 First Line, Safe Effective, Cheap, Orally Administered
 Mechanism Of Action- Displaces Endogenous Oestrogen from Oestrogen
Receptors In The Hypothalamic-pituitary Axis, Which Diminishes Its
Negative Feedback And Increases The Secretion Of GnRH and thus
Gonadotrophins.
 Regimen and monitoring - 50 mg per day for five days following A
spontaneous or progestin-induced withdrawal bleeding.
 Starting from day 2, 3, 4 or 5 of the cycle was not shown to influence the
results
 Duration of treatment- generally limited to six (ovulatory cycles) with
maximum of 12 in total

26. SYNDROME (PCOS)
CC IN COMBINATION
 With Tamoxifen (20mg) : no significant difference in ovulation and
pregnancy rates
 With Ketoconazole (400mg) : no difference in single pregnancy, multiple
pregnancy, miscarriage rates
 With Bromocriptine (7.5mg) : no difference in pregnancy and ovulation
rates
 With Dexamethasone (2mg) : 3-fold increase benefit in pregnancy rate
 With COCP : increased ovulatory and pregnancy rates but no difference
in miscarriage rate
 With B-HCG : no difference in pregnancy and spontaneous abortion rates

27. SYNDROME (PCOS)
FAILURE OF TREATMENT
 Clomiphene resistance – failure to ovulate
 Clomiphene failure – failure to achieve pregnancy
SIDE EFFECTS
 Usually well tolerated dose-dependent
 Related to its estrogenic and anti-estrogenic properties:
 hot flushes, breast discomfort, abdominal distension, nausea, vomiting,
nervousness, sleeplessness, headache, mood swings, dizziness, hair loss
and disturbed vision

28. SYNDROME (PCOS)
2. Tamoxifen
 A Triphenylethylene derivative with a structure similar to CC.
 The suggested dose in ovulation induction is 20-40 mg daily, beginning on
cycle day 3 for 5 days
 Efficacy and safety of Tamoxifen is similar to CC ovulation rates, with no
significant difference in pregnancy rates per cycle, and no difference in
incidence of miscarriage rates.
 While ovulation induction has been shown, Tamoxifen is not licensed for
that purpose and patients should be counseled for its off-label use

29. SYNDROME (PCOS)
 INSULIN SENSITIZING AGENTS:
1. Metformin
 In theory, improves insulin resistance and consequently ovulatory status.
 Regimen- 500 mg tds or 850 mg bd with meals, titrated.
 May provide an alternative for obese patients with clomiphene
resistance.
 Metformin can be offered to obese and non-obese anovulatory women
with PCOS
 Nevertheless, the use of metformin as a preferred ovulation induction
agent in obese women remains a matter of controversy
 Another potential advantage of metformin is that it may have a weight
reducing effect, although this also remains a matter of controversy.
 Avoids the increased risk of multiple pregnancies (4-11%), and ovarian
cancer (prolonged use more than 12 months) associated with
clomiphene

30. SYNDROME (PCOS)
EFFICACY
(a) Metformin monotherapy
 Metformin used alone improves the ovulation rate and clinical pregnancy
rate compared with placebo or no treatment, but not the live birth rate.
 Compared with CC, metformin gives lower ovulation rate and clinical
pregnancy rate and a non-significant trend of lower live birth rate.
 There are no difference in the miscarriage rate and the multiple
pregnancy rate between the two treatments
(b) Metformin co-treatment with CC
 Co-treatment with metformin and CC compared with CC only improves
the ovulation rate and clinical pregnancy rate in obese patients but not in
non-obese patients
 Improves live birth rates inclusive in CC resistant women only

31. SYNDROME (PCOS)
SIDE EFFECTS
 dose-dependent G.I symptoms
 Lactic acidosis is a rare though serious complication, and hence
metformin should not be prescribed to patients with renal, hepatic or
major cardiovascular disease or hypoxia.
2. Use of other insulin sensitizing agents: rosiglitazone and pioglitazone.
 rosiglitazone improved ovulation rate but result in a higher incidence of
weight gain
 On the other hand, these drugs are classified as FDA category C.
 There is no data on the role of pioglitazone in fertility treatment

32. SYNDROME (PCOS)
AROMATASE INHIBITORS:
Letrozole, 3rd generation AI
 gaining in popularity as an agent for ovulation induction in patients with
PCOS.
 Its use in combination with gonadotrophin in ovarian stimulation
protocol for patients, in whom high oestradiol level would be
contraindicated, for example breast cancer patients, is also advocated
 does not have the anti-oestrogenic effects and has a much shorter half
life (~45hrs) [CC: 5-7days]
 Use in ovulation induction is an off-label use.

33. SYNDROME (PCOS)

34. SYNDROME (PCOS)
REGIMEN AND MONITORING
 The regimen is 2.5 to 5 mg per day for five days from day 3-7 of the
period, or as a single dose of 20 mg on day 3 of the period.
 A prolonged duration for 10 days has being evaluated.
SIDE EFFECTS
 Letrozole is well tolerated.
 Fatigue, nausea, constipation, diarrhea, headache, drowsiness and
dizziness are common side effects.
 Multiple pregnancy rate was significantly lower in Letrozole, both 2.5 mg
daily or 5 mg daily, comparing with CC treatment as the letrozole
treatment gave more monofollicular development comparing with CC

35. SYNDROME (PCOS)
GONADOTROPHINS
MECHANISM OF ACTION
The use of exogenous gonadotrophins is to overcome the FSH threshold
required for the follicular development

36. SYNDROME (PCOS)
REGIMENS
 First line therapy for anovulatory patients who have failed to ovulate or
conceive after clomiphene citrate treatment
 Extremely effective in both World Health Organization (WHO) group
II/polycystic ovary syndrome (PCOS) patients and in WHO group
I/hypogonadotrophic hypogonadal patients (WHO, 1973; Balen et al.,
1994)
 Drug dose should be individualized to get the best result.
 ‘Soft’ protocols developed to minimize the risk of multiple ovulation

37. SYNDROME (PCOS)
 “Conventional dose step-up” regime:
. 75-150 iu/day started on day 2-3 of the cycle, is increased by 75
iu/day every 3-5 days till ovarian response is evident.
. compared to the “chronic low-dose step up” approach:
. duration of stimulation is shorter but the incidence of multiple
pregnancy and OHSS is higher, especially in patients with PCOS.
 Chronic low-dose, step-up protocol:
. currently the recommended protocol in many centers worldwide
. low starting dose (37.5-75 IU/day) for at least 10-14 days and the
daily dose is increased by 37.5 IU at weekly intervals up to a maximum of
225 IU/day.
. Once 1 to 2 dominant follicles reach 18 mm in mean diameter, hCG is
given at a dose of 5000-10000 IU to induce ovulation.

38. SYNDROME (PCOS)
 Step-down protocol:
. Aim is to mimic the physiological changes of normal cycles.
. FSH injection started at 150 IU/day starting day 2-3 of the cycle and
ovarian response is monitored by transvaginal scanning every 2-3 days.
. dose is continued until a dominant follicle ≥10mm is seen on scanning,
then ↓ to 112.5 IU/day followed by a further decrease to 75 iu/d 3 days
later
. continued until hCG is administered to induce ovulation. Hence it
requires more intense monitoring than the step up protocol
. shorter duration of stimulation compared to the step up protocol, but a
higher rate of multifollicular development and OHSS as well as a lower
ovulation rate.
. pregnancy rate is comparable between the two regimes.

39. SYNDROME (PCOS)
CONCOMITANT USE:
1. With GnRH agonists (Goserelin)
 Starting on day 21 of cycle prior to gonadotrophin administration will
lower the tonic high LH concentrations during the follicular phase
 prevents the occurrence of premature LH surges. This may be used in
patients with a previous history of premature luteinisation.
 ↑se cost
2. With CC
 lessen the overall cost by ↓ the amount of gonadotrophin needed.
 CC 100mg daily from days 2–6 for follicular recruitment, then
gonadotrophin 150IU daily or on alternate days to promote follicular
growth

40. SYNDROME (PCOS)
 ↓se the gonadotrophin requirement by up to 50%, hence cost.
 used in anovulatory patients who have endogenous gonadotrophins.
MONITORING OF OVARIAN RESPONSE
 to allow for adjustment of the gonadotrophin dose
 timing the hCG injection for ovulation trigger
 and cancellation of cycles with excessive response.
 both serum oestradiol concentrations and ultrasound examination are
commonly used for monitoring purposes.

41. SYNDROME (PCOS)
HIGH RESPONDERS
enlarged ovaries, large no of follicles, elevated serum estradiol
(>3000pg/ml)
(A) Coasting
. To continue GnRH agonist
. No gonadotrophin stimulation
. To give hCG once oestradiol level is within the normal range
(B) To cancel the treatment cycle, higher rate in women with BMI >25kg/m²
(C) Follicular puncture, oocyte retrieval with IVF
(D) Ovarian electrocautery with follicular aspiration
(E) Embryo cryopreservation (used in next cycle)
(F) Avoiding use of hCG for luteal support (progesterone used)
(G) Use of recombinant LH preparations with short half life.

42. SYNDROME (PCOS)
POOR RESPONDERS
fewer follicles (<3) serum oestradiol <500pg/ml
. To use higher dose of gonadotrophin stimulation
. To decrease the doses of GnRH agonists
. To use GnRH antagonists, early onset of action and longer half life, in late
follicular phase, prevent LH surge and does not interrupt folliculogenesis
SIDE-EFFECTS
Serious complications of gonadotrophin therapy include:
 ovarian hyperstimulation syndrome
 multiple pregnancy.
 Other complications include local reaction at the site of the injection
 rarely anaphylactic reaction, perhaps due to the protein content of the
urinary products. Switch to recombinant FSH preparations

43. SYNDROME (PCOS)
GONADOTROPHIN-RELEASING HORMONE (GnRH)
MECHANISM OF ACTION
 GnRH administered in a pulsatile fashion
 restores the normal pattern of gonadotrophin secretion of a spontaneous
menstrual cycle, leading to the development of a single dominant follicle.
 Hypogonadotropic patients of normal or low weight are the best
candidates for this treatment.
 A cumulative pregnancy rate of 80% after six cycles and up to 93% after
12 has been reported.
 It is recommended to continue this therapy for at least 12 cycles in the
absence of other subfertility factors

44. SYNDROME (PCOS)
REGIMEN AND MONITORING
 SC/IV route through a small butterfly cannula using a small battery-
operated pump which delivers 2.5–20.0mcg per bolus at 60-120 minute
intervals.
 The IV route is preferred by some because more physiological LH profiles
and higher ovulatory rates result when GnRH is administered
intravenously.
 Higher dosage (10 mcg per bolus) given at lower intervals (120 minutes)
are just as effective as lower dosage (2-5mcg per bolus) given at a higher
rate (every 60-90 minutes)
 Treatment can be monitored by regular serum oestradiol measurements
and pelvic ultrasound at regular intervals.
 Couples are advised to have regular intercourse during the treatment
cycle.

45. SYNDROME (PCOS)
 The luteal phase has to be supported, either by continuing with the same
regimen of pulsatile GnRH administration or using exogenous hcg
injections.
 Zoladex 3.6mg SC every 28days, and a vial costing about N30000
SIDE-EFFECTS
 Multiple pregnancy . This risk can be greatly reduced if lower pulse
dosages are employed at a lower frequency for the first cycle.
 OHSS has never been described with pulsatile GnRH administration.
 Patients may be reluctant to use the pulsatile GnRH therapy because of
inconvenience, worry about pump failure and the problems of the needle
being left in situ for a long time (e.g. displacement, local reaction,
infection)

46. SYNDROME (PCOS)
SURGICAL INDUCTION OF OVULATION
 second-line treatment modality for PCOS women who fail to respond to
CC
 Wedge resection of ovary; discarded.
 Laparoscopy ovarian drilling; uses monopolar diathermy
. minimal tissue handling
. less risk of adhesions (10-20%)
. further reduced with use of periovarian coolant [ 1L Adept℗ solution
instilled into pouch of douglas]
. Rules of 4: number of diathermy points minimized to 4 per ovary for 4
seconds at 40watts.
. adhesions formed is fine and of little clinical significance

47. SYNDROME (PCOS)
 Laser vaporization; using carbon dioxide, argon or Nd:YAG crystal lasers
. multiple attempts of pregnancy allowed
. monofollicular development
. reduced miscarriage rate
. assessment of the pelvic pathology and tubal status at the same
setting.
. no OHSS reported in the randomized trials in the LOD groups.
. no difference in ovulation rate and clinical pregnancy rate after
unilateral or bilateral ovarian drilling.
. cheaper option in PCOS women resistant to CC than urinary or
recombinant gonadotropin treatment cycle

48. SYNDROME (PCOS)
SIDE-EFFECTS
 need for general anaesthetic and surgery
 adhesion formation
 risk of premature ovarian failure are of concern
Other treatment modalities:
 Assisted reproduction; IVF, in vitro maturation of oocytes
 Adoption
RISKS OF OVULATION INDUCTION
 Multiple pregnancies
 OHSS
 Ovarian cancer

49. GROUP III
 OOCYTE DONATION
considered for women with premature ovarian failure or ovarian failure
following chemotherapy or radiotherapy, bilateral salpingo-
oophorectomy, and gonadal dysgenesis
 ADOPTION

50. TREATMENT OPTIONS FOR WHO GROUP IV
(HYPERPROLACTINAEMIA)
 found in 15% of women with anovulation, and in 75% of women with
both anovulation and galactorrhoea
 High levels of prolactin interfere with the pulsatile release of GnRH from
the hypothalamus. This, in turn, interferes with pituitary gonadotrophin
secretion, resulting in oestrogen-deficient amenorrhoea and subfertility.
 Sustained hyperprolactinaemia, with levels of greater than 1000 mU/l*
needs evaluation, including pituitary imaging.
Causes include:
 Microadenoma; rarely, macroadenoma of the pituitary
 Idiopathic (pituitary neoplasm too small, <5mm, to be seen on CT scan)
 Hypothyroidism, renal or hepatic dysfunction
 Dopaminergic antagonists, such as Phenothiazines
 Physiological factors, such as pregnancy, lactation and stress

51. TREATMENT OPTIONS FOR WHO GROUP IV
(HYPERPROLACTINAEMIA)
 Women with polycystic ovaries; not PCOS (about 9% of women with
polycystic ovaries have a raised prolactin level)
INDICATIONS FOR TREATMENT
 hyperprolactinaemia results in a hypo-oestrogenic state, threatening
skeletal integrity, treatment is advocated in all young women, even if
infertility is not an issue.
 In older women, bone density scanning is a useful indicator to see
whether treatment would be beneficial.
TREATMENT MODALITIES
1. Medical therapy:
 mainline of treatment; first-line treatment is the use of dopamine
agonists, lowers prolactin concentration and cause shrinkage of a
prolactinoma if present.
 Bromocriptine 2.5 to 20 mg in divided doses 2-3 times a day

52. TREATMENT OPTIONS FOR WHO GROUP IV
(HYPERPROLACTINAEMIA)
 If pregnancy occurs while a woman is taking a dopamine agonist, the
current practice is to stop the drug.
 However, in women with large prolactinomas that may enlarge in
pregnancy, this may be unnecessary; weighing the risk-benefit ratio.
2. Surgery:
 trans-sphenoidal pituitary adenomectomy is seldom indicated in the
presence of a prolactinoma because of high recurrence rate and
possibility of panhypopituitism.
 may be indicated for women with large macroadenomas resistant to drug
treatment or where, despite normalisation of prolactin levels, no tumour
shrinkage is seen.
3. Radiotherapy
 is used very infrequently and is considered only if both medical and
surgical treatments fail or are contraindicated.

53. COMPARATIVE ANALYSIS OF OVULATION INDUCTION
DRUGS
OVULATION RATES PREGNANCY
RATES
LIVE BIRTH RATES SIDE EFFECTS
CLOMIPHENE
CITRATE
73% per cycle 36% per cycle 29% per cycle Estrogenic and anti-estrogenic, OHSS,
Dose-dependent, multiple pregnancy
TAMOXIFENE Similar to CC Similar to CC Similar to CC No incidence of OHSS or multiple
pregnancy
METFORMIN Lower than CC Lower than CC Similar to CC G.I. dose-dependent, lactic acidosis,
multiple pregnancy rate similar to CC
LETROZOLE 70-84% per cycle 20-27% per cycle Similar to CC Drowsiness, multiple pregnancy rate
significantly lower than CC
GONADOTROPHINS Higher than CC but
similar in diff types
Comparable to CC,
similar in diff types
Higher than CC but
similar in diff types
Serious risk of OHSS multiple
pregnancy and OHSS, local reaction
GnRH Agonists Higher than CC 80% after 6 cycles;
93% after 12 cycles
Higher than CC Multiple pregnancy rates 3.5-13.5% in
1st cycle. NO OHSS in pulsatile admin.
SURGICAL METHOD
(LOD)
Comparable to
gonadotrophins
Comparable to
gonadotrophins
Comparable to
gonadotrophins
↓est multiple pregnancy rate, risk of
surgery & anaesthesia, adhesions. No
OHSS

54. STUDY
 HISTORY:
Mrs. C. B is 32 years old, oligomenorrheic with confirmed polycystic ovaries
by USS. Her last period was 6 weeks prior to presentation and she is
uncertain as to when her next period will be. She presents to us for
treatment of primary infertility of 3 years' duration. Her husband is 34 years
old, fit and well, with no significant past history of note. He has had one
child aged 7 years from a previous relationship. Other causes of her
infertility were effectively ruled out in the detailed history.
 EXAMINATION:
Mrs. C. B has a BMI of 31 and has no abnormalities detected on an
abdominal or pelvic examination, and her husband's recent semen analysis
is within normal limits.

55. STUDY
 INVESTIGATIONS:
1. Pregnancy test : Negative
2. Hormone assays: Day 3 FSH: 6.8 i.u/l (Day 2-5: 0.5-14.5 i.u/l)
Day 3 LH: 3.2 i.u/l (Day 2-5: 1-11 i.u/l)
Testosterone: 4.1nmol/l (0.8-3.1nmol/l)
Day 21 Progesterone 15 nmol/l
 DIAGNOSIS
Anovulatory infertility due to polycystic ovarian syndrome (PCOS).
Anovulation is shown by the low progesterone level, and PCOS is
suggested her increased BMI, oligomenorrhoea, polycystic ovaries on
USS, increased androgen levels and increased LH.

56. STUDY
 TREATMENT:
1. Adequate Counselling on nature of her infertility
2. Advise weight reduction
3. Induced a withdrawal bleed with oral progesterone
4. Gave clomiphene at a dose of 50mg daily for 5 days, starting on
second day of her bleed
5. Timed sexual intercourse
 FOLLOW UP
After three cycles of clomifene at the 50mg dose, Mrs. C.B returned
with a Positive Pregnancy Test, and she is presently booked in our
Antenatal clinic.

57. TEASER
 Laparoscopic ovarian drilling (LOD) is associated with an increased risk of
multiple Pregnancy
 Premature ovarian failure is irreversible
 More triplets, quadruplets and quintuplets are born as a result of in vitro
fertilisation/intracytoplasmic sperm injection (IVF/ICSI) than ovulation
induction
 50% of all women ON CLOMIPHENE achieving pregnancy do so on the 50
mg dose
 OHSS does not occur in the absence of luteinisation by human chorionic
gonadotrophin or luteinizing hormone (LH)
 OHSS is seen more often in women who are obese
 Evidence suggests that recombinant FSH results in better pregnancy rates
than purified FSH

58. PROPOSED PROTOCOL FOR TREATMENT OF NORMOGONADOTROPHIC ANOVULATION IN LTH OGBOMOSO
 See Attached Leaflet
 A CLINICAL SCHEMATIC APPROACH

59. NT
 The work was supported by my Supervisor, Dr. Oluseyi
Atanda. I thank him for his patience, encouragement
and insightful corrections.
 My Senior registrars for their understanding and
support.
 All my fellow registrars; worthy of mention, Dr. Bajowa,
for the many corrections and additions and suggestion
of materials to include.
 Dr. O.F Ojo for her proof-reading and ensuring I
complete in a timely manner.
 There is no conflict of interest

60. CES
 RCOG STRATOG Module 8 Fertility and Reproductive Medicine
 HKCOG Guidelines; Guideline on ovulation induction, March 2011
 The Journal of Clinical Endocrinology & Metabolism 91(3):760–771,
 Gougeon A1998 Ovarian follicular growth in humans: ovarian ageing and
population of growing follicles. Maturitas 30:137–142
 Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E. Clomiphene and
anti-oestrogens for ovulation induction in PCOS.Cochrane Database Syst
Rev2009: CD002249.
 Balen AH, Michelmore K. What is polycystic ovary syndrome? Are
national views important?HumReprod2002;17:2219-27
 Managing Anovulatory infertility BMJ 2007;335:663-6
 Comparison of tamoxifen and clomiphene citrate for ovulation induction:
a meta-analysis Steiner A Z, Terplan M, Paulson R J

61. CES
 levels of evidence and grading: RCOG recommendation for ovulation
induction 2011
 Infertility: RCOG guidelines 2009
 Reproductive Endocrinology for the MRCOG and Beyond, Adam Balen,
2nd edition ©2007
 Textbook of gynaecology D.C. Dutta, 5th edition ©2008
 Comprehensive gynaecology in the tropics, E.Y. Kwawukume, E.J
Emuveyan ©2002
 Management of the infertile couple: an evidence-based protocol, Reprod
Biol Endocrinol. 2010; 8: 21.
 World Health Organization. Report of the Meeting on the Prevention of
Infertility at the Primary Health Care Level. WHO, Geneva; 1983.
WHO/MCH/1984.4.
 Ovarian reserve tests J. Hum. Reprod Sci . 2011 Sep-Dec; 4(3): 108–113

62. CES
 Ovulation induction, Current Obstetrics & Gynaecology (2004)14, 261–
268
 Homburg R. Polycystic ovary syndrome- from gynaecological curiosity to
multi system endocrinopathy. Hum Reprod 1996; 11: 29-39
 Role of metformin in the treatment of infertility in PCOS, Anju Sinha &
Mr William Atiomo. 2004
 Gonadotrophin induction of ovulation; obstetrics, gynaecology, and
reproductive medicine 17:7; 2010
 Balasch J. The role of FSH and LH in ovulation induction: current concepts
and the contribution of recombinant gonadotropins. in: Gardner DK,
weissman A, Howles CM, Shoham Z, eds. Textbook of assisted
reproductive techniques – laboratory and clinical