Prof. Mahmoud Zakherah Prof of Obstetrics and Gynecology,

Women’s Health Hospital Assiut mszakhera@yahoo.com

2017

Definitions Infertility

Subfertility

Sterility

Physiological backgrounds Hypothalamus

Gonadotrophin-releasing hormone (GnRH)

pulsatile secretionPituitary

FSHLHProlactin

Ovary EstradiolProgesteroneAMH

Physiological backgrounds Menstrual cycle Ovarian cycle

Ovarian cycle

RecruitmentSelectionDominanceOvulation

Estradiol surge 36h LH surge- 36h -+ve feedback mechanism Ovulation------fertilization—implantation

Ovarian cycle

Unripe follicle

Ripening follicle

Ovulation Corpus luteum

Regression of Corpus luteum

Etiology of infertility

Ovulatory disordersOvulatory disorders are a common

cause of infertility 20% , which in most cases is treatable with ovulation induction agents.

The goal of therapy in these women is monofollicular development and subsequent ovulation.

Ovulatory disordersThe method of ovulation

induction selected by the clinician should be based upon the underlying cause of anovulation and the efficacy, costs, risks, and potential complications associated with each method as they apply to the individual woman.

Diagnosis of Ovarian factor

Diagnosis of Ovarian factor

Investigations Ovulation monitoring: (transvaginal

sonography (follicle 18mm) U/S: folliculometry

Midluteal progesterone: (day 21) >3 ng/ml, >10 ng/ml

Premenstrual biopsy : (PEB): Secretory changes (not done)---???????

Endometrial scratching

Ovulation monitoring Folliculometry Trilaminar endometrium

Anovulation

WHO Classification of Anovulation WHO type 1 (hypogonadotropic hypogonadism),

can be caused by any lesion affecting the pituitary or hypothalamus and affecting gonadotropin production

WHO type 2 (normogonadotropic hypogonadism) is by far the commonest cause of anovulation and is most commonly caused by polycystic ovarian syndrome.

WHO type 3 (hypergonadotropic hypogonadism) is usually an indication of ovarian failure.

1- WHO Group - I (Hypogonadotropic hypogonadism)

Hypothalamic pituitary failure (5 to 10 %)These patients present with primary (Kallman’s)

or secondary amenorrhoea (Sheehan’s syndrome), anorexia.

They have very low serum oestradiol due to low FSH and LH secretion from the pituitary gland (hypogonadotrophic hypogonadism).

-ve progestagen challenge test .

WHO Group- IEtiology Hypothalamic--(Kallmann's syndrome) Pituitary (sheehan’syndromeTreatment Intact pituitary function Pulsatile GnRHPituitary dysfunction Human menopausal gonadotrophins (HMG) Human chorionic gonadotrophin (HCG) 

Pulsatile GnRHThis treatment is suitable for women with intact

pituitary gland and especially for those with idiopathic hypogonadotrophic hypogonadism and weight loss-related amenorrhoea.

Computerized minipump at pulse intervals of between 60 and 180 min.

Low rate of multiple pregnancy and OHSS

WHO Group 1 Evidence

They should be offered pulsatile gonadotrophin-releasing hormone or gonadotrophins (HMG) because these are effective in inducing ovulation. ( B)

2- WHO Group II (hypothalamic pituitary dysfunction (70 to 85 %(

Hypothalamic pituitary dysfunctionEugonadotrophic=NormogonadotrophicThis includes a heterogeneous group of patients who

can present either with regular cycle oligomenorrhoea, or even amenorrhoea.

The midluteal serum progesterone is low, FSH levels are in the normal range and prolactin is normal.

Most of these patients are likely to have PCOS.

WHO Group II (hypothalamic pituitary dysfunction (70 to 85 %)

Treatment I-Non pharmacologic Weight loss and exercise life style modification

II–Pharmacologic Antiestrogens as CC tamoxifen or combinationHuman gonadotrophinsInsulin sensitizersDopamine agonistsAromatase inhibitorsIII - Surgical induction of ovulation

(LOD)

I-Non Pharmacologic Induction

Of Ovulation

Non Pharmacologic Induction of ovulation

LIFESTYLE THERAPIES and Weight reduction Body mass index (BMI) is more representative of body fat

and is calculated from weight in kg/height squared in m.Overweight is defined as BMI >=25 kg/m2Obesity is BMI >=30 kg/m2Lifestyle modification is the first form of therapy,

combining behavioral (reduction of psychosocial stressors), dietary, and exercise management.

Reduced-energy diets (500–1000 kcal/day reduction) are effective options for weight loss and can reduce body weight by 7% to 10% over a period of 6 to 12 months.

LIFESTYLE THERAPIES and Weight reduction

Ovarian function is dependent on weight. Low body-fat content is associated with

hypothalamic hypogonadism. Central body fat is associated with

insulin resistance and contributes to ovarian dysfunction in many women with polycystic ovarian syndrome (PCOS).

.

LIFESTYLE THERAPIES and Weight reductionLifestyle modification in overweight infertile

women with PCOS leads to a reduction of central fat and improved insulin sensitivity, decreased hyperandrogenemia, lowered luteinizing hormone (LH) concentrations, and restoration of normal fertility in many cases (Hoeger, 2001; Kiddy, 1992).

Even a 5 to 10 percent reduction in body weight has been shown to be successful in these women (Crosignani, 2003; Kiddy, 1992; Pasquali, 1989

LIFESTYLE THERAPIES and Weight reduction Apart from diet, exercise can also improve

insulin sensitivity. Weight loss and exercise are inexpensive and

should be recommended as first-line management of obese women with PCOS.

Environmental toxinsSmokingCaffeine Stress

Non Pharmacologic Induction of ovulation

Evidence Weight loss, exercise, and lifestyle modifications

have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A)

Morbidly obese women should seek expert advice about pregnancy risk. (III-A)

II- Pharmacologic Induction

of Ovulation

Aim of induction of ovulation

Controlled Ovarian Stimulation (WHO 1&2)

Controlled ovarian hyperstimulation (IVF)

Augmentation of ovulation (unexplained infertility)

Methods of inductionMethods of induction

Anti estrogens (CC-tamoxifen(

HMG

FSH

GnRH

TTT of PRL

Insulin-sensit izing drugs

LOD IN PCOS

1-anti estrogens

ClomipheneCitrate (CC)

Tamoxifen

A. Clomiphene citrate (CC(Clomiphene citrate is a standard treatment for

induction of ovulation in these patients with ovulatory dysfunction..

The standard dosage is 50 -100 milligrams (mg) of clomiphene per day for five consecutive days.

Ovulation at a high rate (70–90%) and, although the pregnancy rate is lower (30–40%)(LH levels and or the antiestrogenic effects).

Clomiphene citratePharmacokinetics

Absorption: Absorbed readily from the GI tract. Distribution: May undergo enterohepatic recirculation or may be stored in body fat. Metabolism: Metabolized by the liver.

Excretion: Half-life is about 5 days. Drug is excreted principally in feces via biliary elimination

Clomiphene citrate (CC(

Start

1 to 7 days WithdrawalOn amenorrhea ( no pregnancy ) Basal scan

Clomiphene citrate (CC(

RepeatBack to back cycles

Washout cycle in between

Clomiphene citrate (CC(Monitoring triple 7

E2 after 7 Ds from last pill.Serum progesterone 7 days later.B hCG 7 days later.

A. Clomiphene citrate (CC( Evidence. Patients with polycystic ovary syndrome should

be offered clomifene citrate (or tamoxifen) as first-line therapy for up to 12 months because it is likely to induce ovulation(A).

Risk of multiple pregnancy (7% to 9%)with ovulation induction using clomiphene citrate (I-A).

Clomiphene citrate (CC(A Cochrane meta-analysis (2009) ; There is no increase in spontaneous

abortion or congenital abnormalities in CC-induced pregnancies.

Evidence of benefit than placebo

Clomiphene failure Ovulation failure (CC resistant) Those who do

not respond to 150 mg per day are considered to be clomifene resistant (10–30%).

Conception failure (due to indésirable effets of CC or due to un diagosed causes).

Decreasing endometrial thickness and endometrial perfusion which affect implantation

Dryness of cervical mucosa which affects sperms motility

High follicular phase LH

Clomiphene failure Extended CC theapy (100 mg/day for days 7-10 days)

Combined therapy :

CC and Dexamethazone (Congenital adrenal hyperplasia) CC and Growth hormone CC and Gonadotrophins (minimal stimulation ) Prior Ocs then Cc treatment Cc and dopamine agonists Cc and NAC CC and ketoconazole CC and metformin CC and Estrogens(Estradiol or phytoestrogens ) Cc plus Tamoxifen (Zakherah etal .2010)

Nitric oxide donors and CCConcomitant use of Isosorbid

monoitrate ( Effox 10-20 mg) tab with CC seems to improve the ovulation and pregnancy rates in the patients with PCOS with no significant increase in side effects as compared with CC alone.

Sildenafil and CCSildenafil being a selective PDE5 isoenzyme inhibitor

enhances the effect of nitric oxide by inhibiting PDE5, which is responsible for degradation of cGMP.

Sildenafil citrate 25 mg orally or vaginally in induction of ovulation lead to increase number of follicles, endometrial thickness and so increase pregnancy rate.

Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.

Dexamethazone

Cc 100 3-7 DLow dose 0,5 mg High dose 2mg ( 1mg /12 5-14).

N Acetylcysteine and CCNAC as an adjuvant to CC for induction of ovulation

can improve the ovulation and pregnancy rates in PCOS patients and may also have some beneficial impacts on endometrial thickness. NAC is well-tolerated, safe, and inexpensive and may be a novel adjuvant treatment to improve the induction of ovulation outcomes in PCOS patients. NAC exerts its effect due to its mucolytic and metabolic actions especially insulin sensitising effect

Tamoxifen plus CC

B. Tamoxifen

As CC (action regimen, ect…(

20-40 mg/d.

Adverse effect on Cx. mucus

The usual starting dose is 20 mg daily given for five days starting on day3 to 5 of the cycle.Evidence In a randomized comparison between Tamoxifen and Clomiphene, no significant difference between ovulation and pregnancy rates were observed .

2-Insulins Sensitizing DrugsMetformin (500 mg tds or 850 mg bd

with meals)Monotherapy

Metformin used alone improves the ovulation rate (OR 2.12; 95% CI 1.5–3.0) and clinical pregnancy rate (OR 3.86; 95% CI 2.18–6.84) compared with placebo or no treatment, but not the livebirth rate (OR 1.0; 95% CI 0.16–6.39)(Cochrane Database of Systematic Reviews 2010).

Combined therapy

Anovulatory women with polycystic ovary syndrome who have not responded to clomifene citrate and who have a body mass index of more than 25 should be Metformin combined with Clomifene citrate because this increases ovulation and pregnancy rates. (A)

MetforminEvidence Metformin combined with Clomiphene citrate

may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone (I-A).

Metformin may be added to Clomiphene citrate in women with Clomiphene resistance who are older and who have visceral obesity (I-A).

Metformin- combined therapy

Clomiphene resistant : Metformin & CC produced significant improvement.

Recent study- Letrozole & Metformin also showed promising results.

3- Gonadotrophins Types

1. HMG2. FSH3. HCG

Gonadotrophins

Indications :Hypogonadotropic (WHO class 1) : anovulatory

women with hypopituitarism or as second-line therapy in women with hypothalamic amenorrhea.

Normogonadotropic (WHO class 2): anovulatory women who have not ovulated or conceived with clomiphene treatment.

Human Menopausal Gonadotropins

)HMG(

Group I anovulation

No response to CC

Adjunct to CC No pregnancy despiteovulation with CC

The first choice in WHO group1The second choice )acts directly on the ovaries( in WHO group2This is associated with a 10% pregnancy rate per cycle but the risk of ovarian hyperstimulation and multiple pregnancies is high

HMG is commercialized in 75 IU ampoules IM )75 IU of FSH and 75 IU of LH(

Protocols Chronic low-dose, step up protocolConventional dose step-upStep down protocol:

Human Menopausal Gonadotropins

Human Menopausal GonadotropinsEvidence Gonadotropin should be considered second-line

therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring.

High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A)

B-Follicle stimulating Hormone

FSH

Predominant FSH)25iuLH( Pure FSH

)> 1iuLH(

Recombinant FSH)no LH(

The 2nd line of therapy in patients with PCOS

Days 7 14 21 28

hCG

150 IU 112.5 IU 75 IU hCG

Foll. ≥ 10 mm

75 IU112.5 IU 150 IU

6 12

75 IU hCG

Foll. ≥ 14 mm

½

75 IU 75 IU 112.5 IU 150 IU

Chronic low dose step up

Step down

Sequential

C-Human Chorionic Gonadotropin (hCG)  

Surrogate LH surge -Ovulation triggering Final oocyte maturationHCG 5000- 10,000 IU S/C or IM

Ovulation will usually occur about 36 hours after hCG is administered gate LH surge

GnRH agonist may be used to trigger ovulation especially in antagonist protocols

5-Dopamine agonists

Normal Serum Prolactin ----400-500 mlU/ml (20-25 ng/ml

Hyperprolactinaemia can be found in 15% of women with anovulation, and in 75% of women with both anovulation and galactorrhoea.

The presence of hyperprolactinemia should always be confirmed by several measurements of serum prolactin.

5-Dopamine agonists

An MRI of the head should be done in any woman with hyperprolactinemia in whom the cause is not obvious (eg, neuroleptic drug therapy, primary hypothyroidism).

Primary hypothyroidism---prolactin-stimulating action of thyrotrophin-releasing hormone (TRH).

Subclinicah hypothyrodism TSH ≤ 2,5 IU

5-Dopamine agonistsThere are three treatment options:Dopamine agonists The first-line treatment is the use of dopamine agonists which lower

prolactin concentration and cause shrinkage of a prolactinoma if present.

Surgery Transphenoidal pituitary adenomectomy is seldom USED

Radiotherapy is used very infrequently

Dopamine agonistsBromocriptine is by far the most widely used drug

orally (2.5 to 20 mg divided into two or three doses) or intravaginally

Cabergoline, a prolactin-lowering drug with long-lasting effect, most patients require doses as low as 0.5 to 1.0 mg per week.

Lisuride 0.2mg tablets Quinagolide hydrochloride (NORPROLAC) non

Ergot dopamine agonist(0.025 mg per day and increase to 0.075 mg per day )

5-Dopamine agonistsEvidence Women with ovulatory disorders due to

hyperprolactinaemia should be offered treatment with dopamine agonists.

Consideration should be given to safety for use in pregnancy and minimising cost when prescribing. (A).

It is recommended that the minimal length of dopamine agonist therapy in patients wit prolactinoma should be one year

6- GnRH Types Pulsatile GnRh in women with clomifene citrate-

resistant polycystic ovary syndrome is a research context.(A)

GnRH Agonists should not be offered (A). GnRH Antagonists should not be offered (A).

In IVF agonist or antagonist protocols

Pulsatile GnRh Pulsatile GnRH(60 to 90 minutes) administration is

indicated for women with hypogonadotropic hypogonadal anovulation (WHO class 1) who have normal pituitary function

The intravenous route appears superior to the subcutaneous route

Chances of multifollicular development and ovarian hyperstimulation are low

7-Aromatase InhibitorsLetrozole (Femara) and anastrozole (Not FDA approved for

IO)

Letrozole (third-generation aromatase inhibitor ) 2.5 mg OD/BD on D 3-7 A prolonged duration for 10 days has been evaluated) FDA approved for postmenopausal breast cancerLacks unfavorable effects on endometrium seen with

CC and has shorter half life.Initial evidence is encouraging and results are similar

to clomifene, but larger trials are required

7-Aromatase InhibitorsAromatase inhibitor has the following

advantages over CC:

1.It does not deplete ERs throughout the body

2.It keeps the hypothalamopituitary axis intact

3.It is short acting (45 min half-life).

7-Aromatase Inhibitorsletrozole ensures improved endometrial thickness, cervical mucus, monofollicular, and better folliculogenesis

WHO Group 3(Hypergonadotropic hypogonadism(

10 to 30 %,these women present with primary or secondary amenorrhea

low endogenous estrogen and highly elevated FSH levels

Premature ovarian insufficiency (POI) (depleted)

Resistant ovary syndrome (unresponsive )

No value of laparoscopy or biopsy

Hypergonadotropic hypogonadism

Intermittent and unpredictable ovarian function and spontaneous pregnancies have been reported in approximately 5–10% of cases subsequent to the diagnosis

DHEA therapy 75mg/day

Unexplained infertilityUnexplained infertility Inability to conceive after one year with routine (standard, basic) investigations of infertility showing no abnormality. incidence: 10-20%Women should be informed that clomifene citrate treatment increases the chance of pregnancy.DHEA therapy 75mg/dayIVF may the ideal solution especially in age above 30 ys old.

ConclusionsOvarian stimulation is the fundamental tool of

subfertility treatment.Different options pose challenges.Choice depends on doctors expertise and

patients condition.Aim is to Increases the pregnancy rate.Judicious monitoring to avoid complications.