ANOVULATORY INFERTILITY

DR ALOBO G. I.
OBST. & GYN DEPT
FMC MKD
 OUT LINE

INTRODUCTION
CLASSIFICATION OF ANOV INFERTILITY
TYPES OF PRESENTATION
DIAGNOSIS
MGT
COMPLICATIONS
CONCLUSION
 INFERTILITY IS INABILITY OF A COUPLE TO
ACHIEVE PREGNANCY AFTER ONE YEAR OF
NORMAL, REGULAR, UNPROTECTED COITUS.

PROBLEM IS AS OLD AS MANKIND!

SUBFERTILITY, CHILDLESSNESS – SYNONYMS

STERILITY – ABSOLUTE, CONOTES IRREVERSIBILITY


FECUNDITY – PROBABILITY OF LIVE BIRTH IN ONE

MENSTRUAL CYCLE

FECUNDABILITY – PROBABILITY OF CONCEPTION PER MONTH OF

EXPOSURE

80% of couples will conceive within 1 year of unprotected intercourse

~86% will conceive within 2 years

.
INCIDENCE: VARIES 10% (20-30%)

TYPES:
PRIMARY – HAS NEVER HAD A PREGNANCY

SECONDARY – HAS HAD A PREVIOUS

PREGNANCY IRRESPECTIVE OF OUTCOME

WACS REVISION COURSE (UCH) FEB 2007,

Source: EKELE.
SOCIAL EFFECTS OF INFERTILITY

Marital discord
Stigma
Ostracisation
Violence against women
Loss of inheritance

WACS REVISION COURSE (UCH) FEB 2007,

Source: EKELE.
 PRESENTATION

AMMENORHEA
OLIGOMENORRHEA
IRREGULAR MENSTRUATN
GALACTORRHEA
OBESITY / WT LOSS
VIRILISM
 ANOVUL INFERT

CLASSIFICATION BASED ON PHYSIOLOGY

1. HYPOYTHAL ANOV
2. PITUT ANOV
3. OVARIAN ANOV
4. INTERGRATIVE ANOV
5. SYSTEMIC ANNOV
 Ovarian Dysfunction

Three main causes of dysfunction

 WHO TYPE 1-Hypogonadotrophic, hypoestrogenic (central).
Hypothalamic &Pituaitory disorders, hypothyroidism, normo-
prolactinemia,


 WHO TYPE 2-Normogonadotrophic, hypo gonadism (e.g. PCOS), adult

onset CAH, adrenal dx, luteal phase defect, normoprolactinemia

 WHO TYPE 3- Hypergonadotrophic, hypoestrogenic (POF), resistant

ov synd, decreased ov reserve, ovarian diseases, normoprolactinemia

 HYPER PROLACTINEMIA (central)

 HYPO THALAMIC/pituitary

DIAG OF EXCLUSN
GnRH PULSE
NN OR REDUCED GONADO TROPHINS & NEG
PROG CHALLENGE TEST IS DIAGNOSTIC
CAUSES- exercise, wt loss, ano nervosa, kall man
synd, stress, non funct hypotha/pit tm
Low features of hypo estrogenism
Sheehan’s synd
Drugs
 HYPER PROLACTINEMIA

EFF ON PULSATILE RELEASE OF GnRH

ON OVARIAN STEROIDOGENESIS
CAUSES
PIT TMs, HYPOTHYR, EMPTY SELLA SYN,
TRANSECTN OF PIT STALK
DRUGS – Phenothiaznes, TCA depessants, OCPs
STRESS, SEX, NIPPLE STIM, H. Zoster
PX WITH GALACTOREA without amm 15% h- prol,
with amm 75%.
 THYROID DX

HYPER & HYPO

ALTERATN IN ESTROGEN & ANDR MET & GONADOTROPH SEC

HYPO MORE DEMONST cf HYPER

BOTH ASSOC WITH DEC LIBIDO

NO BENEFIT OF TSH TREATMENT ON INFERT IN AUTHY PX

NO BENEFIT EVEN IN SUB CLIN HYPOTHY ( INCREASE TSH)

TREATMENT BENEFIT ON INFERT IN CLINICAL HYPOTHY WITH ANOVULTN

IN PAN HYPOPIT CORRECT ADRENAL INSUFF B4 THROID HORMONE

 Definition of PCOS

1. Europe view:- Ultrasound profile.

2. USA view (NIH ): - Endocrine Profile.
3. Rotterdam definition PCOS (2003).
 Rotterdam , May
2003 Definition
PCOS could be defined when at least two of the
following three features are present, after
exclusion of other etiologies :
(i) Oligomenorrhea and or Anovulation
(ii) Hyperandrogenism and/or hyperandrogenemia.
(iii) Polycystic ovaries (sonar).
 Ultrasonic Criteria of PCO

At least one of the following:

12 or more follicles measuring 2–9 mm in diameter,
increased ovarian volume (>10 cm3).
 If there is a follicle >10 mm in diameter, the scan
should be repeated at a time of ovarian quiescence in
order to calculate volume and area.
The presence of a single PCO is sufficient to provide
the diagnosis.
 The distribution of follicles and a description of the
stroma are not required for diagnosis.
Stein and Leventhal  Polycystic ovarian
They were the first to syndrome
 Biochemical, clinical and
recognize an association endocrinological abnormalities
between the presence of  Syndrome O
polycystic ovaries and  Ovarian confusion and Ovulation
signs of hirsutism disruption caused primarily by
amenorrhea Over nourishment and
(oligomenorrhea, obesity) Overproduction of insulin
Polycystic Ovarian  In reality PCOS, infertility, and
Disease other health problems may be all
consequences of syndrome O
Primary ovarian disorder
come to be known as
polycystic ovarian disease
What is The significance of polycystic-
appearing ovaries versus normal
appearing ovaries in patients with
PCOS??

The presence of polycystic-appearing ovaries

usually correlates with the presence of insulin
resistance (Richard J 2002).
 Etiology

Speculation:
 Complex interaction of genetic ,epigenetic and
environmental factors.
 Recently ,PCOS is mediated by ghrelin
( gastric peptide which is orexigenic and adipogenic)
 Pathogenesis
Three major hypothesis (culprits ) may all
interact:
Insulin resistance ( central player).
Hyperandrogenism & (altered
Gonadotropins)
Recently (target genes) :
 Genes encoding Inflammatory cytokines.
 INSR genes.
 IR ( Metabolic or Syndrome x) What is?

Insulin acts like a key which can open a door on the

cell's surface.

cells do not have enough insulin receptor sites and

cannot effectively burn glucose .

this excess glucose is then sent to the liver where it is

converted to fat.
 The Central Player ( Insulin
Resistance )
Pregnancy Aging Drugs Lifestyle

Insulin Upper abdominal

Genetics Resistance obesity

Increased lipid storage

Hyperinsulinemia
PCOS
Altered lipoprotein &
Altered steroid cholesterol metabolism
hormone metabolism
Proposed APPROACH FOR ttt of PCOS\
Targets for treatment PCOS
Drug Therapy: Insulin-Sensitizing Agents (Metformin)
Potential Advantages
• ↑ glucose tolerance
• ↑ insulin sensitivity
• ↓ blood lipid levels
• ↑ weight loss or stabilization
• Improved fat distribution
• ↓ blood pressure
• ↓ androgen levels
• Restoration of regular menses
• Postponement of diabetes
Potential Disadvantages
Gastrointestinal
disturbance in 1/3 of
patients
Generalized feeling of
unwell ness
Decreased absorption
of vitamin B-12
Lactic acid buildup
 Laparascopic Treatment of Polycystic
Ovaries: Is Its Place Diminishing?
Laparascopic ovarian drilling and Metformin
improve ovulatory dysfunction and pregnancy rate
to a similar extent.
The advantages of Metformin continue beyond
conception:
 It reduces the miscarriage rate
 Decreases the likelihood of developing
gestational diabetes.
 Long Term Risks Of PCOS

CVD Hypertension

Gout Endometrial
Cancer

PCOS
NIDDM Infertility

Gallbladder
Obesity
Disease
 LUTEALMPHASE DEFECT

Defect prog sec in luteal phase

At least two day lag in secretory changes
Decrease in length of sec or amt secreted
Short lut ph < 10 days
Inadeq LP- sub norm prog sec
May contrib 3 -20% of infert esp people with recc
miscarriage. LPD not conf as a cause of infert
Increase in hyper androgenism, exercise,
CCT treated
Diag endomet biopsy single NN enough 4 diag
 ADRENAL DX

ADDISON – auto imm adre insuff

Cushing synd- raised ACTH or autonomous prod of
glucocort. Role in infert unconfirmed, probably assoc
increase estrogen may affect feed back or effect on
pulse GnRH
Distinguish 4m PCOs by dexamethasone supp test
and 24 hrs urine free cortisol. DEXAM 1mg given at
bed time, fasting cortisol is measured in d morning if
< 5mug cush synd is excluded
 ADULT ONSET CAH

May mimic PCOs

Rel def of 21- hydroxylase, 3 b –hydroxy ster def
Features of androgenemia
Familial
Diag – fasting morning 17- hydroxy prog of < 2ng/ ml
ACTH or cosyntropin stimulatn test
RELATIVE ANDROGENICITY – DHT-300, testosterone – 100,
androstenedione – 10, DHEAS -5
Principal androgen produced by adr gld is DHEAS, ovary is
androstendione
21- hydroxylase short arm of Xsome 6. Its gene also called CYP21. CYP21P
is an inactive pseudo gene both int with C4B & C4A both encode C4 gene
Incr serum 17-OHP
 Late onset congenital adrenal hyperplasia
DHEAS > 18mmol/l
17 OH Prog > 6 mmol/l

 Ovarian + adrenal androgen secreting tumours

V. high teslosterone > 6mmol/l

 Cushings Syndrome
- Dexamethsone suppression test
- 24 hours urinary cortisol
- DHEAS > 13 mmol/l
 OVARIAN DYSGENESIS

FAILURE TO MAINTAIN OOCYTES (PRIM

FOLLICLES) IN A STATE OF ARREST UNTIL
PUBERTY
TURNERS SYND MONOSOMY 45 XO
INC FSH
RESISTANT OV SYNDROME. (SAVAGE SYND)
DYSFNAL OVARIAN TUMORS
 PREM OV FAILURE

DEFN-FAILURE OF OVARIAN ESTROGEN

SECRETN IN A WOMAN < 35 YRS
IDIOPATHIC
MULTIFACTORIA – infectns mumps, genetic
IATROGENIC – irradiatn, chemotheraphy
Auto imm disorders ( poly endocrine auto imm dx)
Assoc with aborm galactose metabolism, post men
synd
FSH > 40 Miu, R/O Y- xsome
 DIMINISHED OV RESERVE

DAY 3 FSH > 15 -20mIU/ml

USUALLY EUMENORRHEIC
RESPOND POORLY TO GONADOTROPHIN
CCCT 100mg DAY FSH
OVARIAN RES INVERSELY PROP TO AGE. THO
EFF OF AGE ON FECUNDIBILITY IS
INDEPENDENT OF RESERVE
MAY BE A FACTOR IN UNEXPLAINED INF
 OTHER DISORDERS

SYSTEMIC ANNOVULATION
ACUTE / CHRONIC ILLNESS

POST PILL ANOVULATION 0.2 – 3.4 %

 DIAGNOSIS

HISTORY & EXAMINATN

PREGNANCY
OOCYTES RETRIEVAL
PROGESTERONE CHALL TEST/ FSH & LH

ANNOV AMMENORHEIC- R/O PREGNANCY

100mg PROG IN OIL STAT

10mg MEDROX PROG ACETATE X 5 DAYS

AWAIT WITH DRAWAL BLEEDING AFTER 10 -14 DAYS

INCREASE FSH & LH IN MENOPAUSAL RANGE – R/O

OV DX
LH INCREASE cf FSH SUSPECT PCOs

SUSPECT PIT TM IF ISOLATED INCR IN FSH

 BBT

Cheap and easy, but…

 Inconsistent results
 Provides evidence after the fact (like the old story about the
barn door and the horse)
 May delay timely diagnosis and treatment
 98% of women will ovulate within 3 days of the nadir
 Biphasic profiles can also be seen with LUF syndrome
 Luteal Phase Progesterone

Pulsatile release, thus single level may not be useful

unless elevated
Performed 7 days after presumptive ovulation
Done properly, >15 ng/ml consistent with ovulation

ESTROGEN – PRE OVUL PEAK OF 40 – 100ug/24

hours
Urinary estrone 3 glucoronideE3G . Also ratio of
E3GB with pregnendiol 3@ glucoronide
 Urinary LH Kits

Very sensitive and accurate

Positive test precedes ovulation by ~24 hours, so
useful for timing intercourse
Downside: price, obsession with timing of
intercourse
 CERVICAL MUCUS

CRRV MUCORIA, SPINBERKET (abt 5 – 10 cm extensibilty),

FERNING
3 DAYS B4 AND 3 DAYS AFTER
INSLER SCORE - QTY, SPINBERKET, FERNING APPEARANCE OF
CXCAL OS FOUR PT SCORE OF 0 – 3 IS GIVEN TO PARAMETER .
SCORES OF 10 – 12 IS FAV
MOGHISSI – AMTS, FERNING, SPINB, VISCOSITY, CELLULARITY
BURNS/CARAMEL TEST-MUCUS SPREAD, HEATED OVER FLAME
ALCOHOL LAMP FOR 1 MIN – LIGHT/ DARK BROWN COLOR -
neg,TRANSPERENT COLOR – POSITIVE
SOLUBLE PROTEIN igA, igG. ALBUMIN @1- ANTI TRYP
DECREASE
RELATIVE DECREASE ENZYMES
 VAGINA CHANGES

KARYO PYKNOTIC INDEX INCREASE

2 DAYS AFTER ESTROGEN PEAK

SALIVA- ALK PO4ase INCREASE ALSO N – acety –

b-D-glucosemine. Also saliv ferning
BLD- BASOPHIL REDUCED,LEUC ALK PO4ase,
Cue fertility monitor – saliv and vag electrical
resistance
 Endometrial Biopsy

Invasive, but the only reliable way to diagnose LPD

??Is LPD a genuine disorder???
Pregnancy loss rate <1%
Perform around 2 days before expected
menstruation (= day 28 by definition)
Lag of >2 days is consistent with LPD
Must be done in two different cycles to confirm
diagnosis of LPD
Done using karman syringe
 USS

FOLLICULAR TRACKING
FOLLICULE DIAM 17mm to 26mm
Less accurate diag tool
Usefull in diag luitenized unruptured follicle synd LUFS SA
PERSISTENT echo free dorm follicle 36 hrs after LH surge
LUFS assoc with infert not est as its not usu reccurrent
Adjunct in ART
SKULL X – RAY ( PITUITARY TM)
CT SCAN, MRI 4 MICRO/MACRO ADENOMA IN HYPER
PROLACTINEMIA
 Types of Ov. Stimulation

1. Induction of ovulation.
2. Superovulation.
3. Controlled ovarian
hyperstimulation (COH).
 Drugs for Ov. Stim.
 CC
GONADOTROPHINS:
HMG
highly purified ur FSH
Rec. FSH
Rec LH
 GNRH (PULSATILE).
 GNRHA (INTRANASAL-S.C- I.M)
 GNRH ANTAGONIST (INVOLVED IN
FINAL STEPS OF OOCYTE MATURATION).
 HCG & BROMOCRIPITINE (!?)
 CC
Competitive inhibitor of E2
blocks E receptor in hypothalamus.
GnRH FSH & LH.
Follicles
After last tablet by one W:
Freeing of hypothalamus receptors
from blockage.
Trigger LH surge (response to E2).
 Problems with (cc)
1- long lasting(till 14-22 day of cycle)
2-  subclinical pregnancy loss compared to normal
population
3-  LH sec > FSH  miscarriage
4- (LUF)syndrome(unexplained infertility)
5- Anti E(cx &endometrium)
6-  ectopic (tubal transport)
7- side effect : -Minor (nausea-vomiting-flush skin-
hair loss)
OHS
Multiple pregnancy.
Gonadotropins

Unlike CC – Gn acts
directly on the ovaries.
 GnRH
Natural
-Is a deca peptide ( ten AA ).
-Half life time is 8 min (10 min bursts every
60 min)

Synthetic
 By selective A.A or ethylamide substitutions at
6 and/or 10 (Gly) postions.
 -  affinity for GnRH receptors (100-200
times).
- 1/2 life to 5 hours.
 GnRHa
Routes:
- Intranasal.
- S.C.
- Depot (Longer period + need higher doses Gn+
need more luteal support) (Devreken et al ,1996).
Effect:
- Agonistic (flare up) phase LH & FSH .
- Down regulation (on continuous administration)
Within two weeks).
 protocols

Long
Short
Ultra short
 3RD GENERATION AROMATASE INHIBITORS
offer increased potency, specificity and bette
I-STEROIDAL DERIVATIVES: exemestane
(aromasin) approved in usa.
II-NON-STEROIDAL IMIDAZOLE DERIVATIVES:
fadrozole.
III-NON-STEROIDAL TRIAZOLE DERIVATIVES:
1. Anastrazole (Arimidex)
2. Letrozole (Femara)
Both are approved in USA for the treatment of breast cancer.
 COMPLICATION OF ANOVULATION

EARLY – OHSS, ectopic, multi fetal pregnancy

LATE – ENDOMETRIAL HYP & CA, DM
 Risk factors

 Young age
 Low body weight
 Polycystic ovaries
 High dose of gonadotrophins
 Large no. of oocytes retrieved
 High oestradiol level on day of hcg admin
 Use of hcg for luteal support
 Ensuing pregnancy
 Previous episodes of OHSS
 Prevention of OHSS

 Withholding HCG administration.

 Reduced dose of HCG.

 Administration of rec-LH.

 Freeze the embryos.

 Coasting

 Infusn of albumin
 conclusion

A GOOD UNDERSTANDING OF
ANOVULATION AND ITS MGT WILL
HELP PREVENT ANOTHER WOMAN
FROM LOOSING HER HOME TO
INFERTILITY

Thank you