current management of anovulatory infertility

Current Management of Anovulatory

Infertility

.

PRESENTER: DR O.A EWEDEMI B.SC, MBBSCHAIRMAN: DR O.O.A ATANDA FMCOG

Obstetrics and Gynaecology Dept.LAUTECH Ogbomoso

INTRODUCTION

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

INTRODUCTION

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

PHYSIOLOGICAL BASIS OF OVULATION

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 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.

WHO CLASSIFICATION OF ANOVULATION

Group Description Features Examples

I5-10%

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.

II70-85%

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.

ANATOMIC SITE OF H-P-O 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

PRINCIPLES OF 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


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


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

INVESTIGATIONS

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.

INVESTIGATIONS

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%

INVESTIGATIONS

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.

INVESTIGATIONS

INVESTIGATIONS

Advanced Fertility Center of Chicago

INVESTIGATIONS

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

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

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.

POLYCYSTIC OVARIAN 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.


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


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.


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


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


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


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


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


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


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


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.


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


GONADOTROPHINSMECHANISM OF ACTION

The use of exogenous gonadotrophins is to overcome the FSH threshold required for the follicular development


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


“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.


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.


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


↓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.


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.


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


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


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.


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)


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


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


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

TREATMENT OPTIONS FOR WHO 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

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


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


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.

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



↓est multiple pregnancy rate, risk of surgery & anaesthesia, adhesions. No OHSS

CASE 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.

CASE 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.

CASE 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.

RESPONSE TO TEASER

Laparoscopic ovarian drilling (LOD) is associated with an increased risk of multiple Pregnancy FALSE

Premature ovarian failure is irreversible FALSE More triplets, quadruplets and quintuplets are born as a result of in vitro

fertilisation/intracytoplasmic sperm injection (IVF/ICSI) than ovulation induction FALSE

50% of all women ON CLOMIPHENE achieving pregnancy do so on the 50 mg dose TRUE

OHSS does not occur in the absence of luteinisation by human chorionic gonadotrophin or luteinizing hormone (LH) TRUE

OHSS is seen more often in women who are obese FALSE Evidence suggests that recombinant FSH results in better pregnancy rates

than purified FSH FALSE

PROPOSED PROTOCOL FOR TREATMENT OF NORMOGONADOTROPHIC ANOVULATION IN LTH OGBOMOSO

See Attached Leaflet A CLINICAL SCHEMATIC APPROACH

ACKNOWLEDGMENT

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

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Managing Anovulatory infertility BMJ 2007;335:663-6 Comparison of tamoxifen and clomiphene citrate for ovulation induction:

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