Anovulation: Aetiology and Management Dr. Darron Halliday

Anovulation: Aetiology and Anovulation: Aetiology and ManagementManagement

Dr. Darron HallidayDr. Darron Halliday

Anovulation :Aetiology and ManaAnovulation :Aetiology and Managementgement

OutlineOutline

IntroductionIntroduction Causes suitable for ovulation induction Causes suitable for ovulation induction Causes unsuitable for ovulation Causes unsuitable for ovulation

induction induction Drug inducedDrug induced Diagnosis of anovulatory subfertility Diagnosis of anovulatory subfertility Management of anovulation Management of anovulation


IntroductionIntroduction

Disorders of ovulation account for about 20% -Disorders of ovulation account for about 20% -30% of infertility and often present with 30% of infertility and often present with oligomenorrhoea or amenorrhoeaoligomenorrhoea or amenorrhoea

The majority fall into the WHO group II categoryThe majority fall into the WHO group II category

Many of the treatments are simple and effectiveMany of the treatments are simple and effective

Anovulation can sometimes be treated with Anovulation can sometimes be treated with medical or surgical inductionmedical or surgical induction

ACOG 2002, Fairley and Taylor BMJ 2003




Causes of anovulation suitable Causes of anovulation suitable for ovulation induction for ovulation induction

treatmenttreatment HypothalamicHypothalamic

Low concentration of gonadotrophin Low concentration of gonadotrophin realeasing hormone (hypogonadotrophic realeasing hormone (hypogonadotrophic hypogonadism) hypogonadism)

Weight or exercise related amenorrhoea Weight or exercise related amenorrhoea Kallman's syndromeKallman's syndrome StressStress Idiopathic Idiopathic



treatmenttreatment PituitaryPituitary

• • Hyperprolactinaemia Hyperprolactinaemia

• • Pituitary failure (hypogonadotrophic Pituitary failure (hypogonadotrophic hypogonadism) hypogonadism)

• • Sheehan's syndrome Sheehan's syndrome

• • Craniopharyngioma or hypophysectomy Craniopharyngioma or hypophysectomy

• • Cerebral radiotherapy Cerebral radiotherapy



treatmenttreatment OvarianOvarian

• • Polycystic ovaries Polycystic ovaries

Other endocrineOther endocrine• • Hypothyroidism Hypothyroidism

• • Congenital adrenal hyperplasia Congenital adrenal hyperplasia


Causes suitable for ovulation Causes suitable for ovulation inductioninduction

Hypogonadotrophic hypogonadismHypogonadotrophic hypogonadism is is characterised by a selective failure of the characterised by a selective failure of the pituitary gland to produce luteinising pituitary gland to produce luteinising hormone and follicle stimulating hormone and follicle stimulating hormonehormone

BMI < 20 Kg/mBMI < 20 Kg/m22

gymnasts, marathon runners, ballerinas—may gymnasts, marathon runners, ballerinas—may develop amenorrhoea because of a physiological develop amenorrhoea because of a physiological reduction in the hypothalamic production of reduction in the hypothalamic production of gonadotrophin releasing hormone gonadotrophin releasing hormone


Weight-related amenorrhoeaWeight-related amenorrhoea

Anorexia NervosaAnorexia Nervosa Abnormal body image, intense fear of Abnormal body image, intense fear of

weight gain, often strenuous exerciseweight gain, often strenuous exercise Mean age onset 13-14 yrs (range 10-21 yrs)Mean age onset 13-14 yrs (range 10-21 yrs) Low estradiol Low estradiol risk of osteoporosis risk of osteoporosis Bulemics less commonly have amenorrhea Bulemics less commonly have amenorrhea

due to fluctuations in body wt, but any due to fluctuations in body wt, but any disordered eating pattern (crash diets) can disordered eating pattern (crash diets) can cause menstrual irregularity.cause menstrual irregularity.

Treatment : Treatment : body wt. (Psychiatrist referral) body wt. (Psychiatrist referral)


Causes suitable for ovulation induction Causes suitable for ovulation induction

Sheehan's syndrome - caused by Sheehan's syndrome - caused by infarction of the anterior pituitary infarction of the anterior pituitary venous complex (usually after venous complex (usually after massive postpartum haemorrhage or massive postpartum haemorrhage or trauma)trauma)

Kallman's syndrome- (amenorrhoea Kallman's syndrome- (amenorrhoea with anosmia caused by congenital with anosmia caused by congenital lack of hypothalamic production of lack of hypothalamic production of gonadotrophin releasing hormone). gonadotrophin releasing hormone).


cerebral irradiation cerebral irradiation RX for craniopharyngioma or some RX for craniopharyngioma or some

forms of leukaemia forms of leukaemia may affect the hypothalamus or the may affect the hypothalamus or the

pituitary may resulting in pituitary may resulting in hypogonadotrophic hypogonadism hypogonadotrophic hypogonadism


HyperprolactinaemiaHyperprolactinaemia

caused by a pituitary microadenoma. caused by a pituitary microadenoma.

causes reduction in the production of pituitary causes reduction in the production of pituitary luteinising hormone and follicle stimulating hormone. luteinising hormone and follicle stimulating hormone.

Causes secondary amenorrhoea, galactorrhoea, Causes secondary amenorrhoea, galactorrhoea, headaches or disturbed vision headaches or disturbed vision

treatment with drugs result in subsequent treatment with drugs result in subsequent resumption of menses and fertility resumption of menses and fertility


Polycystic ovary syndromePolycystic ovary syndrome

The most common cause of chronic anovulation (70%) The most common cause of chronic anovulation (70%)

Hyperandrogenism ; Hyperandrogenism ; LH/FSH ratio LH/FSH ratio

Insulin resitance is a major biochemical feature (Insulin resitance is a major biochemical feature ( blood blood insulin levelinsulin level hyperandrogenism ) hyperandrogenism )

Long term risks: Obesity, hirsutism, infertility, type 2 Long term risks: Obesity, hirsutism, infertility, type 2 diabetes, dyslipidemia, cardiovasular risks, endometrial diabetes, dyslipidemia, cardiovasular risks, endometrial hyperplassia and cancerhyperplassia and cancer

Treatment depends on the needs of the patient and Treatment depends on the needs of the patient and preventing long term health problemspreventing long term health problems


Transvaginal scan of a polycystic ovary. Typically 10 or more follicles of <10 mm in diameter ("string of pearls") are in a single transverse or longitudinal section through the ovary. Stromal density and ovarian volume increase


Psychogenic Hypothalamic Psychogenic Hypothalamic AmenorrheaAmenorrhea

Amenorrhea and anovulation a definite Amenorrhea and anovulation a definite history of psychological and history of psychological and socioenvironmental trauma socioenvironmental trauma

Characterized by low to normal basal levels Characterized by low to normal basal levels of serum gonadotropins with normal of serum gonadotropins with normal responses to GnRH, prolonged suppression responses to GnRH, prolonged suppression of gonadotropins in response to estradiol, of gonadotropins in response to estradiol, and failure of a positive feedback response and failure of a positive feedback response to estradiol, increased basal levels of to estradiol, increased basal levels of cortisol and decreased levels of DHEAS cortisol and decreased levels of DHEAS



The mechanism by which emotional states or stressful The mechanism by which emotional states or stressful experiences cause psychogenic amenorrhea is not yet experiences cause psychogenic amenorrhea is not yet established. established.

Higher centers have copious connections with the Higher centers have copious connections with the hypothalamus hypothalamus

Evidence suggests that a cascade of neuroendocrine events Evidence suggests that a cascade of neuroendocrine events that may begin with limbic system responses to psychic that may begin with limbic system responses to psychic stimuli impairs hypothalamic-pituitary activity stimuli impairs hypothalamic-pituitary activity

It has been suggested that increased hypothalamic b-It has been suggested that increased hypothalamic b-endorphin is important in inhibiting gonadotropin secretion endorphin is important in inhibiting gonadotropin secretion



Associated factors Associated factors a history of previous pregnancy lossesa history of previous pregnancy losses stressful life events within the 6-month period stressful life events within the 6-month period

preceding the amenorrheapreceding the amenorrhea poor social support or separation poor social support or separation psychosexual problems and socioenvironmental psychosexual problems and socioenvironmental

stresses during the teenage years stresses during the teenage years have negative attitudes toward sexually related have negative attitudes toward sexually related

body parts, more partner-related sexual body parts, more partner-related sexual problems, and greater fear of or aversion to problems, and greater fear of or aversion to menstruation than do eumenorrheic womenmenstruation than do eumenorrheic women



Treatment.Treatment. The treatment of patients with stress The treatment of patients with stress

induced hypothalamic chronic induced hypothalamic chronic anovulation is controversial. anovulation is controversial.

Psychological therapy and support or a Psychological therapy and support or a change in lifestyle may cause cyclic change in lifestyle may cause cyclic ovulation and menses to resumeovulation and menses to resume

Ovulation induction - as will be Ovulation induction - as will be discussed discussed


Causes unsuitable for ovulation Causes unsuitable for ovulation

inductioninduction Ovarian failureOvarian failure

• • Idiopathic Idiopathic

• • Radiotherapy or Radiotherapy or chemotherapy chemotherapy

• • Surgical removalSurgical removal

• • GeneticGenetic

• • Autoimmune Autoimmune

ChromosomalChromosomal• • Turner's syndrome Turner's syndrome

(45,X) (45,X)

• • Androgen Androgen insensitivity insensitivity syndrome (46,XY) syndrome (46,XY)


Premature Ovarian FailurePremature Ovarian Failure

Ovarian failure before the age of 40 yrs is POF, Ovarian failure before the age of 40 yrs is POF, absence of menses for 3 cycles/6mthsabsence of menses for 3 cycles/6mths

Unfortunately this is an irreversible condition. The Unfortunately this is an irreversible condition. The only treatment option that can result in only treatment option that can result in conception is the use of donated eggs with in conception is the use of donated eggs with in vitro fertilisationvitro fertilisation

Estrogen most effective rx for hot flashes, vag Estrogen most effective rx for hot flashes, vag dryness, urinary s/s, emotional lability (6m-5yrs), dryness, urinary s/s, emotional lability (6m-5yrs), long term: CHD, osteoporosislong term: CHD, osteoporosis


Premature ovarian failurePremature ovarian failure

Serum estradiol < 50 pg/ml and FSH > Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions 40 IU/ml on repeated occasions

10% of secondary amenorrhea10% of secondary amenorrhea Few cases reported, where high dose Few cases reported, where high dose

estrogen or HMG therapy resulted in estrogen or HMG therapy resulted in ovulationovulation

Sometimes immuno therapy may Sometimes immuno therapy may reverse autoimmue ovarian failurereverse autoimmue ovarian failure

Rarely Rarely spont. ovulation (resistant spont. ovulation (resistant ovaries)ovaries)

Treatment: HRT (Treatment: HRT (osteoporosis, osteoporosis, atherogenesisatherogenesis))


Gonadal dysgeneisGonadal dysgeneis

Chromosomally incompetentChromosomally incompetent

- Classic turner- Classic turner’s syndrome (45XO)’s syndrome (45XO)

- Turner variants (45XO/46XX),(46X-- Turner variants (45XO/46XX),(46X-abnormal abnormal X)X)

- Mixed gonadal dygenesis (45XO/46XY)- Mixed gonadal dygenesis (45XO/46XY) Chromosomally competentChromosomally competent

- 46XX (Pure gonadal dysgeneis)- 46XX (Pure gonadal dysgeneis)

- 46XY (Swyer’s syndrome)- 46XY (Swyer’s syndrome)


Gonadal dysgenesisGonadal dysgenesis

Classic Classic

Turner’Turner’ss

TurnerTurner

Variant Variant True True

gonadal gonadal

Dysgenesis Dysgenesis

MixedMixed

Dysgenesis Dysgenesis

phenotypephenotype Female Female Female Female Female Female Ambiguous Ambiguous

Gonad Gonad Streak Streak Streak Streak Streak Streak - Streak - Streak

- Testes- Testes

Hight Hight Short Short - Short - Short

- Normal - Normal Tall Tall Short Short

Somatic Somatic stigmata stigmata

ClassicaClassical l

±± Nil Nil ±±

karyotypekaryotype XOXO XX/XO XX/XO or or

abnormal abnormal X X

46-46-XX(Pure)XX(Pure)

46-XY 46-XY (Swyer)(Swyer)

XO/XYXO/XY


TurnerTurner’s syndrome’s syndrome

•• Sexual infantilism and short stature.Sexual infantilism and short stature.• • Associated abnormalities, webbed Associated abnormalities, webbed

neck,coarctation of the aorta,high-arched neck,coarctation of the aorta,high-arched pallate, cubitus valgus, broad shield-like chest pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low hairline on the with wildely spaced nipples, low hairline on the neck, short metacarpal bones and renal neck, short metacarpal bones and renal anomalies.anomalies.

• • High FSH and LH levels.High FSH and LH levels.• • Bilateral streaked gonads.Bilateral streaked gonads.• • Karyotype - 80 % 45, X0 Karyotype - 80 % 45, X0 - 20% mosaic forms (46XX/45X0)- 20% mosaic forms (46XX/45X0)• • Treatment: HRT Treatment: HRT


Mosaic (46-XX / 45-XO) (Classic 45-XO)

Turner’s syndrome


Ovarian dysgenesis


Androgen insensitivityAndrogen insensitivity

Testicular feminization syndromeTesticular feminization syndrome X-linked trait X-linked trait Absent cytosol receptorsAbsent cytosol receptors Normal breasts but no sexual Normal breasts but no sexual

hairhair Normal looking female Normal looking female

external genitaliaexternal genitalia Absent uterus and upper Absent uterus and upper

vaginavagina Karyotype 46, XYKaryotype 46, XY Male range testosterone levelMale range testosterone level Treatment : gonadectomy Treatment : gonadectomy

after puberty + HRTafter puberty + HRT


PhysiologicalPhysiological

MenarchyMenarchy Peri-menopause/ menopausePeri-menopause/ menopause PregnancyPregnancy Breast feedingBreast feeding


20% of women are irregular cycles20% of women are irregular cycles Greatest variability found in years Greatest variability found in years

following menarche and those following menarche and those preceding menopausepreceding menopause First 5-7 years post menarche are time of First 5-7 years post menarche are time of

increasing regularity and cycle shortening increasing regularity and cycle shortening to normal reproductive patternto normal reproductive pattern

Most consistent cycles between the ages Most consistent cycles between the ages of 20 and 30of 20 and 30

Highest rate of anovulation is <20 and Highest rate of anovulation is <20 and >40>40


Hormonal Changes with Established Hormonal Changes with Established MenopauseMenopause

FSH and LH levels undergo an accelerated rise in the last FSH and LH levels undergo an accelerated rise in the last 2 to 3 years before menopause, with estrogen levels 2 to 3 years before menopause, with estrogen levels declining only within approximately 6 months before declining only within approximately 6 months before menopause. menopause.

After menopause, when ovarian follicles are depleted, After menopause, when ovarian follicles are depleted, FSH and LH levels continue to rise. FSH and LH levels continue to rise.

Eventually, there is a 20-fold increase in FSH levels and Eventually, there is a 20-fold increase in FSH levels and an approximately threefold increase in LH levels, both of an approximately threefold increase in LH levels, both of which peak in the first 1 to 3 years after menopausewhich peak in the first 1 to 3 years after menopause

In comparison, ovarian estrogen production does not In comparison, ovarian estrogen production does not continue beyond menopause, when ovarian follicles and continue beyond menopause, when ovarian follicles and their estrogen-producing granulosa cells are depletedtheir estrogen-producing granulosa cells are depleted


Lactational amenorrheaLactational amenorrhea

Elevated prolactin levels and a reduction Elevated prolactin levels and a reduction of gonadotropin-releasing hormone from of gonadotropin-releasing hormone from the hypothalamus during lactation the hypothalamus during lactation suppress ovulation suppress ovulation

This leads to a reduction in luteinizing This leads to a reduction in luteinizing hormone (LH) release and inhibition of hormone (LH) release and inhibition of follicular maturationfollicular maturation

Ovulation usually returns after 6 months Ovulation usually returns after 6 months despite continuous nursingdespite continuous nursing


DrugsDrugs

OCPOCP Antipsychotic Antipsychotic


STEROIDAL STEROIDAL CONTRACEPTIONCONTRACEPTION

oestrogens and progestogens basedoestrogens and progestogens based The oestrogen in most pills The oestrogen in most pills

ethinyl estradiol ethinyl estradiol using the lowest possible using the lowest possible The 'traditional' progestogens The 'traditional' progestogens

ethynodiol, levonorgestrel ethynodiol, levonorgestrel and and norethisteronenorethisterone The newer progestogens The newer progestogens

desogestrel desogestrel (DSG), (DSG), gestodene gestodene (GSD) and (GSD) and norgestimate norgestimate bind more specifically to bind more specifically to progesterone receptorsprogesterone receptors


STEROIDAL STEROIDAL CONTRACEPTIONCONTRACEPTION

Modes of actionModes of action Inhibition of ovulation due to negative Inhibition of ovulation due to negative

feedback on the hypothalamo-pituitary-feedback on the hypothalamo-pituitary-ovarian axis ovarian axis

Induction of changes in cervical mucus, Induction of changes in cervical mucus, endometrium, myometrium and fallopian endometrium, myometrium and fallopian tubestubes

makes them hostile to sperm and unfavourable makes them hostile to sperm and unfavourable for ovum transplant and implantationfor ovum transplant and implantation


Psychotropic MedicationsPsychotropic Medications

Antipsychotics may block dopamine receptors in the pituitary Antipsychotics may block dopamine receptors in the pituitary prolactin-secreting cells and prevent dopamine-induced reduction prolactin-secreting cells and prevent dopamine-induced reduction of prolactin releaseof prolactin release

Hyperprolactinemia can result in galactorrhea, amenorrhea, Hyperprolactinemia can result in galactorrhea, amenorrhea, irregular menses, and anovulation; in men, impotence and irregular menses, and anovulation; in men, impotence and azoospermia, with or without lactation and gynecomastia, can azoospermia, with or without lactation and gynecomastia, can occur.occur.

The treatment of choice is reduction of the antipsychotic dosage or The treatment of choice is reduction of the antipsychotic dosage or discontinuation of therapy. discontinuation of therapy.

If adjustments to the antipsychotic dosage fail to resolve If adjustments to the antipsychotic dosage fail to resolve symptoms, the dopamine agonists bromocriptine and amantadine symptoms, the dopamine agonists bromocriptine and amantadine may be tried.may be tried.


INVESTIGATION



Hypogonadotrophic Hypogonadotrophic hypogonadismhypogonadism

A careful history A careful history surgery, radiotherapy, massive haemorrhage, surgery, radiotherapy, massive haemorrhage,

lack of smell, exercise, and eating habitslack of smell, exercise, and eating habits

a body mass index measurement will reveal a body mass index measurement will reveal the cause. the cause.

concentrations of luteinising hormone, concentrations of luteinising hormone, follicle stimulating hormone, and estradiol follicle stimulating hormone, and estradiol will be lowwill be low



A serum prolactin concentration of > 1000 A serum prolactin concentration of > 1000 IU/l is diagnostic and usually indicates a IU/l is diagnostic and usually indicates a microadenoma. microadenoma.

MRI or CT should be arranged to detect MRI or CT should be arranged to detect whether a macroadenoma is present. whether a macroadenoma is present.

Patients with a macroadenoma must have Patients with a macroadenoma must have their visual fields checked their visual fields checked


HyperprolactinemiaHyperprolactinemia

LH and FSH concentrations are usually at the lower LH and FSH concentrations are usually at the lower end of the normal range with a low estradiol end of the normal range with a low estradiol concentration. concentration.

Test for hypothyroidism and pregnancy Test for hypothyroidism and pregnancy

In hypothyroidism thyrotropin releasing hormone In hypothyroidism thyrotropin releasing hormone may stimulate prolactin secretion in addition to may stimulate prolactin secretion in addition to thyrotropin releasing hormone from the anterior thyrotropin releasing hormone from the anterior pituitary pituitary


Polycystic ovary Polycystic ovary syndromesyndrome

A transvaginal ultrasound scan of the pelvis will A transvaginal ultrasound scan of the pelvis will confirm the diagnosis. confirm the diagnosis.

In 80% of women testosterone concentration are In 80% of women testosterone concentration are > 2.4 nmol/l > 2.4 nmol/l

LH concentrations are raised (> 10 IU/l) in 45-LH concentrations are raised (> 10 IU/l) in 45-70% of women with the syndrome70% of women with the syndrome


Management of anovulation Management of anovulation

Treating specific Treating specific causescauses


Change of weightChange of weight

Women with polycystic ovary syndrome Women with polycystic ovary syndrome who are overweight (body mass index > who are overweight (body mass index > 30) should be advised to lose weight. 30) should be advised to lose weight.

Exercise, weight loss- reduces insulin Exercise, weight loss- reduces insulin and free testosterone levels, resulting and free testosterone levels, resulting in improved menstrual regularity, in improved menstrual regularity, ovulation, and pregnancy rates. ovulation, and pregnancy rates.


Change of weightChange of weight

Women who are underweight (body mass Women who are underweight (body mass index < 20) should be encouraged to gain index < 20) should be encouraged to gain weightweight

No infertility treatment should be offered No infertility treatment should be offered until their body mass has returned to the until their body mass has returned to the lower limits of normal. lower limits of normal.



Bromocriptine is safe and commonly used.Bromocriptine is safe and commonly used. starting dose of 1.25 mg (taken with food) starting dose of 1.25 mg (taken with food)

at night for the first fortnight and then at night for the first fortnight and then increased to 2.5 mg for another fortnight. increased to 2.5 mg for another fortnight.

The prolactin level should be checked, and The prolactin level should be checked, and if the level is below 1000 IU/l, the dose if the level is below 1000 IU/l, the dose should be maintained. should be maintained.


Side effectsSide effects postural hypotension, nausea, vertigo, headachepostural hypotension, nausea, vertigo, headache

Cabergoline and quinagolide are newer Cabergoline and quinagolide are newer long acting dopamine agonists with fewer long acting dopamine agonists with fewer side effects. side effects.

Once prolactin < 1000 IU/l associated with Once prolactin < 1000 IU/l associated with ovulation in 70-80% of womenovulation in 70-80% of women


HypothyroidismHypothyroidism

In hypothyroidism thyrotropin releasing In hypothyroidism thyrotropin releasing hormone may stimulate prolactin secretion hormone may stimulate prolactin secretion in addition to thyrotropin releasing in addition to thyrotropin releasing hormone from the anterior pituitaryhormone from the anterior pituitary

Correction of the hypothyroidism with Correction of the hypothyroidism with thyroxine replacement allows thyroid thyroxine replacement allows thyroid stimulating hormone and prolactin levels to stimulating hormone and prolactin levels to return to normal, releasing the suppression return to normal, releasing the suppression to gonadotrophin secretion and ovulation to gonadotrophin secretion and ovulation


Antioestrogen treatment: Antioestrogen treatment: ClomifeneClomifene

Clomifene acts by blocking oestrogen receptors in Clomifene acts by blocking oestrogen receptors in the pituitary the pituitary

leads to an increased production of follicle leads to an increased production of follicle stimulating hormone, which then stimulates stimulating hormone, which then stimulates development of one or more dominant folliclesdevelopment of one or more dominant follicles


Clomiphene Citrate - dose Clomiphene Citrate - dose regimenregimen

After spontaneous menses or the induction of After spontaneous menses or the induction of menses with a progestin withdrawal, clomiphene is menses with a progestin withdrawal, clomiphene is started on cycle day 3, 4, or 5 at 50 mg daily for 5 started on cycle day 3, 4, or 5 at 50 mg daily for 5 days. days.

Get Progesterone checked on D21Get Progesterone checked on D21

Not ovulating to 100mg-150mg per dayNot ovulating to 100mg-150mg per day

Maximum recommended no of ovulatory cycles - 6Maximum recommended no of ovulatory cycles - 6


Clomiphene CitrateClomiphene Citrate

Ultrasound monitoring, because risk of Ultrasound monitoring, because risk of ovarian hyperstimulation syndrome ovarian hyperstimulation syndrome

70% of women with PCO will ovulate 70% of women with PCO will ovulate

conception rate of 40-60% at six months. conception rate of 40-60% at six months.

The incidence of twins is around 10%, and The incidence of twins is around 10%, and triplets 1%. triplets 1%.


Downsides to ClomipheneDownsides to Clomiphene

Unpleasant side effects Unpleasant side effects irritability, hotflashes, abdominal irritability, hotflashes, abdominal

discomfort, visual disturbancesdiscomfort, visual disturbances Multiple pregnanciesMultiple pregnancies Endometrial hypotrophy esp. when Endometrial hypotrophy esp. when

used for > 6 monthsused for > 6 months Hostile sperm cervical mucous Hostile sperm cervical mucous

interactionsinteractions



Tamoxifen and Oligo-ovulationTamoxifen and Oligo-ovulation

Dose of 20-40mg twice daily from day 2-5 Dose of 20-40mg twice daily from day 2-5 Similar side effects Similar side effects SERM with some estrogenic effects on the SERM with some estrogenic effects on the

endometriumendometrium May improve sperm/mucus interactionsMay improve sperm/mucus interactions Similar rates of ovulation and pregnancySimilar rates of ovulation and pregnancy OHSS rare and usually resolves on its ownOHSS rare and usually resolves on its own Incidence of twins slighty increasedIncidence of twins slighty increased

Boostanfar et al 2001


Aromatase InhibitorsAromatase Inhibitors

• Letrozole: Letrozole: an oral, reversible, no-an oral, reversible, no-steroidal aromatase inhibitor. steroidal aromatase inhibitor.

• Dose: 2.5 mg/d from day 3-7Dose: 2.5 mg/d from day 3-7 Results in ovulation in 9/12 in Results in ovulation in 9/12 in

Clomiphene resistant PCOClomiphene resistant PCO Addition of letrozole may reduce Addition of letrozole may reduce

dose and increase response to FSHdose and increase response to FSH


Mechanism of action:

1. Release of the estrogen negative feedback, increase GnTR, stimulate ovarian follicle development

2. Increase sensitivity of follicles to FSH.

Advantages of letrozole over CC:

Because of the short half life (45h) & absence of ER depletion

No effect on the endometrial thickness or cervical mucous

Letrozole is effective for increasing follicle recruitment in UI (Mitwally & Casper,2000)

Letrozole can replace CC in patients with UI undergoing ovulation induction & IUI (Sammour,2001) .

LetrozoleLetrozole


MetforminMetformin

doses of 1500 mg a day similar effect doses of 1500 mg a day similar effect to weight loss) NB increase dose to weight loss) NB increase dose slowlyslowly

Lowers insulinLowers insulin Lowers testosteroneLowers testosterone Increases SHBGIncreases SHBG Improves HDL:LDL ratioImproves HDL:LDL ratio


MetforminMetformin

Systematic review of metformin for Systematic review of metformin for PCO: 12 RCT’s, 2 cohort studies and 16 PCO: 12 RCT’s, 2 cohort studies and 16 case seriescase series

Metformin alone improves menstrual Metformin alone improves menstrual cyclicitycyclicity

Metformin plus CC improves Metformin plus CC improves pregnancy ratespregnancy rates

Costello, Eden 2003Costello, Eden 2003


Surgical inductionSurgical induction

Laparoscopic ovarian diathermy or "drilling" Laparoscopic ovarian diathermy or "drilling" has replaced wedge resection of the ovaries has replaced wedge resection of the ovaries in women with polycystic ovary syndrome. in women with polycystic ovary syndrome.

At laparoscopy, five to six diathermy or laser At laparoscopy, five to six diathermy or laser punctures are made in the ovary.punctures are made in the ovary.

If too much ovarian tissue is destroyed there If too much ovarian tissue is destroyed there is a potential risk of premature ovarian is a potential risk of premature ovarian failure in the future, although this risk is still failure in the future, although this risk is still being evaluated.being evaluated.


Ovarian Cautery for PCOOvarian Cautery for PCO

8 trials comparing 8 trials comparing ovarian drilling to other ovarian drilling to other interventions ( CC, interventions ( CC, FSH, GnRHa/FSH)FSH, GnRHa/FSH)

Similar miscarriage Similar miscarriage rate, 22%rate, 22%

Multiple pregnancy Multiple pregnancy rates post cautery FSH rates post cautery FSH seems reduced 0% vs seems reduced 0% vs 10%10%


Human Gonadotropins – Human Gonadotropins – Endocrinology OverviewEndocrinology Overview

Link between hypothalamic-pituitary Link between hypothalamic-pituitary axis and the ovaryaxis and the ovary

Required at threshold levels for Required at threshold levels for follicular developmentfollicular development


Human GonadotropinsHuman Gonadotropins

Control of gonadotropin release Control of gonadotropin release occurs through pulsatile occurs through pulsatile hypothalamic production of hypothalamic production of gonadotropin releasing hormone gonadotropin releasing hormone (GnRH)(GnRH) Pulses vary over the course of the menstrual Pulses vary over the course of the menstrual

cycle.cycle. The timing and amplitude of pulses determine The timing and amplitude of pulses determine

gonadotropin release from the pituitary. gonadotropin release from the pituitary.


Types of GonadotropinsTypes of Gonadotropins

In females, the reproductive axis is In females, the reproductive axis is responsive to two main gonadotropin responsive to two main gonadotropin types:types: Follicle Stimulating Hormone (FSH)Follicle Stimulating Hormone (FSH) Luteinizing Hormone (LH)Luteinizing Hormone (LH)


Pulsatile gonadotrophin releasing Pulsatile gonadotrophin releasing hormonehormone

May be suitable in hypothalamic May be suitable in hypothalamic cause of amenorrhoeacause of amenorrhoea

Mechinical device delivers a Mechinical device delivers a pulse of gonadotrophin pulse of gonadotrophin releasing hormone releasing hormone subcutaneously every 90 subcutaneously every 90 minutes, and this usually leads minutes, and this usually leads to unifollicular ovulation. to unifollicular ovulation.

Local reactions may occur at the Local reactions may occur at the injection site. injection site.

Conception rates are similar to Conception rates are similar to those in the normal population those in the normal population at around 20-30% per cycle and at around 20-30% per cycle and 80-90% after 12 months' use80-90% after 12 months' use

Exogenous GonadotropinExogenous Gonadotropin TherapyTherapy


Exogenous Gonadotropin Exogenous Gonadotropin TherapyTherapy

Patient Types Patient Types Substitution - hypogonadal womenSubstitution - hypogonadal women Stimulation – women with hypothalamic Stimulation – women with hypothalamic

dysfunctiondysfunction Regulation - oligo-anovulatory womenRegulation - oligo-anovulatory women Hyperstimulation therapy – women undergoing Hyperstimulation therapy – women undergoing

Assisted Reproductive Technology proceduresAssisted Reproductive Technology procedures


Exogenous Gonadotropin Exogenous Gonadotropin TherapyTherapy

• Objective: simulate a normal Objective: simulate a normal menstrual cyclemenstrual cycle

• AAction: override the hypothalamic-ction: override the hypothalamic-pituitary axis and direct:pituitary axis and direct:

the onset and duration of follicular the onset and duration of follicular development development

the timing and number of follicles the timing and number of follicles that reach maturitythat reach maturity

the production of gonadal steroidsthe production of gonadal steroids


Follicle stimulating hormone Follicle stimulating hormone injectionsinjections

used in women with hypothalamic-pituitary used in women with hypothalamic-pituitary causes of anovulation, and for women with causes of anovulation, and for women with polycystic ovary syndrome who have failed to polycystic ovary syndrome who have failed to respond to or conceive using clomifene. respond to or conceive using clomifene.

monitored by reproductive specialists with access monitored by reproductive specialists with access to ultrasonography and tertiary care facilitiesto ultrasonography and tertiary care facilities

complicated by ovarian hyperstimulation complicated by ovarian hyperstimulation syndrome and high order multiple pregnancy syndrome and high order multiple pregnancy


Approved urinary derived Approved urinary derived gonadotropins and recombinant gonadotropins and recombinant

gonadotropinsgonadotropinsTrade Name Established Name

Pergonal Menotropins (LH, FSH)

Humegon® Menotropins (LH, FSH)

Repronex Menotropins (LH, FSH)

Metrodin HP (Fertinex)

Urofollitropin (FSH)

Bravelle Urofollitropin (FSH)

Gonal-F Follitropin alpha (FSH)

Follistim Follitropin beta (FSH)


Types of Types of Gonadotropin Gonadotropin

Therapy MarketedTherapy Marketed

Recombinant human Recombinant human gonadotropinsgonadotropins follitropin alfa (Gonal-f®) follitropin alfa (Gonal-f®) follitropin beta, (Follistim®)follitropin beta, (Follistim®) chorionic gonadotropin alfa (Ovidrel®). chorionic gonadotropin alfa (Ovidrel®).


A Typical U.S. Gonadotropin A Typical U.S. Gonadotropin Treatment Protocol Treatment Protocol

Baseline serum estradiol (EBaseline serum estradiol (E22) level ) level Baseline ultrasound scanBaseline ultrasound scan Administer daily for 7 - 10 daysAdminister daily for 7 - 10 days Repeat ERepeat E2 2 level and ultrasound level and ultrasound

approximately every 2 to 3 days until approximately every 2 to 3 days until follicular maturity is achievedfollicular maturity is achieved

Administer human chorionic Administer human chorionic gonadotropin (hCG) to induce ovulationgonadotropin (hCG) to induce ovulation


75 IU 75 IU 112.5 IU 150 IU

Days 7 14 21 28

hCG

Chronic Low Dose (CLD): S. Franks et al.

Step Down (SD): B. Fauser et al.

Sequential (SE): J.N. Hugues et al.

150 IU 112.5 IU 75 IU hCG

Foll. ³ 10 mm

75 IU112.5 IU 150 IU

6 12

75 IU hCG

Foll. ³ 14 mm

½

FSH administration FSH administration regimensregimens


Cumulative pregnancy Cumulative pregnancy rates for rates for hypogonadotropic hypogonadotropic anovulatory women anovulatory women treated with treated with gonadotropins.gonadotropins.

(From Lunenfeld B, Insler V. Human (From Lunenfeld B, Insler V. Human gonadotropins. In: Wallach EE, Zacur HA, eds. gonadotropins. In: Wallach EE, Zacur HA, eds. Reproductive medicine and surgery. St. Louis: Reproductive medicine and surgery. St. Louis: Mosby-Year Book, 1995:617)Mosby-Year Book, 1995:617)


Pregnancy rate

Nugent et al Cochrane 2000

Study GnRH-a + Gonadotropin Gonadotropin

Fleming 1988

14/40 5/38

Homburg 1990

5/57 6/65

Hompes 1986

0/5 4/6

Total 19/102 12/106

Anovulation :Aetiology and ManaAnovulation :Aetiology and Managementgement Nugent et al Cochrane 2000

Study GnRH-a + Gonadotropin Gonadotropin

Bachus 1990

1/33 2/26

Homburg 1990

8/57 5/65

Hompes 1986

0/3 0/3

Total 9/93 7/94

OHSS rate


Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS)(OHSS)

The ovarian hyperstimulation The ovarian hyperstimulation syndrome is an iatrogenic syndrome is an iatrogenic complication of ovulation-induction complication of ovulation-induction therapy therapy

incidence of 0.5 to 5 percent among incidence of 0.5 to 5 percent among patients undergoing ovulation-patients undergoing ovulation-induction therapy. induction therapy.


Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS)(OHSS)

Causes:Causes: 1. increasing stimulated follicles and retrieved 1. increasing stimulated follicles and retrieved

oocytes;oocytes; 2. presence of PCOS;2. presence of PCOS; 3. high estrogen level;3. high estrogen level; 4. HCG injection;4. HCG injection; Pathophysiology:Pathophysiology: 1. local and systemic increase in capillary 1. local and systemic increase in capillary

permeability;permeability; 2. Inflammatory responses;2. Inflammatory responses;


Clinical finding:Clinical finding: OHSS OHSS

(1) Mild OHSS (1) Mild OHSS (a) Grade 1, abdominal distention and discomfort (a) Grade 1, abdominal distention and discomfort (b) Grade 2, plus nausea, vomiting, and/or diarrhea (b) Grade 2, plus nausea, vomiting, and/or diarrhea associated with ovarian enlargement of 5-12 cm associated with ovarian enlargement of 5-12 cm (2) Moderate OHSS (2) Moderate OHSS (a) Grade 3, manifestations of the mild form plus (a) Grade 3, manifestations of the mild form plus US evidence of ascites US evidence of ascites (3) Severe OHSS (3) Severe OHSS (a) Grade 4, features of moderate OHSS plus clinical evidence (a) Grade 4, features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax or breathing difficulties of ascites and/or hydrothorax or breathing difficulties (b) Grade 5, changes in blood volume, increased blood (b) Grade 5, changes in blood volume, increased blood

viscosity viscosity due to hemoconcentration, coagulation abnormalities due to hemoconcentration, coagulation abnormalities and impaired renal function with oliguria and impaired renal function with oliguria Golan et al., Obstet Gynecol Surv 1989; 44:430-40Golan et al., Obstet Gynecol Surv 1989; 44:430-40


Ovarian hyperstimulation syndrome (OHSS)Ovarian hyperstimulation syndrome (OHSS)

Examinations:Examinations:

1. Complete blood account, renal and liver function;1. Complete blood account, renal and liver function;

2. Prothrombin time, partial thromboplastin time;2. Prothrombin time, partial thromboplastin time;

3. Chest X-ray;3. Chest X-ray;

4. Trans-vaginal ultrasound;4. Trans-vaginal ultrasound;

5. Oxygen saturation;5. Oxygen saturation;

6. Fluid balance;6. Fluid balance;

7. Serum HCG measurement;7. Serum HCG measurement;

8. 8. Pelvic exam is contraindicatedPelvic exam is contraindicated;; Treatment:Treatment:

1. Prevention of OHSS;1. Prevention of OHSS;

2. Follow-up: Vital signs, fluid intake and output measurement;2. Follow-up: Vital signs, fluid intake and output measurement;

3. Admission to hospital;3. Admission to hospital;


Management of OHSSManagement of OHSS

MildMild No need to admit No need to admit Increase oral fluid intake Increase oral fluid intake Follow up at regular intervals and report if symptoms worsen Follow up at regular intervals and report if symptoms worsen

ModerateModerate Admit to hospital and assess daily Admit to hospital and assess daily Start thromboprophylaxis and maintain until patient is Start thromboprophylaxis and maintain until patient is

dischargeddischarged Monitor liver function, urea and electrolytes, full blood count, Monitor liver function, urea and electrolytes, full blood count,

and clotting and clotting SevereSevere

Strict fluid balance with input of 3 L or moreStrict fluid balance with input of 3 L or more May need intravenous albuminMay need intravenous albumin Drain ascites or pleural effusion if symptomatic Drain ascites or pleural effusion if symptomatic



References References

Peter Braude Paula Rowell, Assisted conception. III—Problems with assisted conception BMJ 2003;327:920-Peter Braude Paula Rowell, Assisted conception. III—Problems with assisted conception BMJ 2003;327:920-

923 (18 October), doi:10.1136/bmj.327.7420.920923 (18 October), doi:10.1136/bmj.327.7420.920 Anovulation Diana Hamilton-Fairley, Alison Taylor BMJ 2003;327:546-549 (6 September), Anovulation Diana Hamilton-Fairley, Alison Taylor BMJ 2003;327:546-549 (6 September),

doi:10.1136/bmj.327.7414.546 doi:10.1136/bmj.327.7414.546

Marken PA, Haykal RF, Fisher JN. Management of psychotropic-induced hyperprolactinemia.Clin Pharm. 1992 Marken PA, Haykal RF, Fisher JN. Management of psychotropic-induced hyperprolactinemia.Clin Pharm. 1992 Oct;11(10):851-6 Oct;11(10):851-6

ACOG Practice Bulletin; Management of Infertility Caused by Ovulatory Dysfunction; ACOG NUMBER 34, FEBRUARY 2002ACOG Practice Bulletin; Management of Infertility Caused by Ovulatory Dysfunction; ACOG NUMBER 34, FEBRUARY 2002

Documents

Anovulation: Aetiology and Management Dr. Darron Halliday