Dr reji's ovarian reserve testing

Ovarian Reserve Testing

Dr REJI MOHAN,MD,DNBConsultant in OBS GYN & INFERTILITY

Assistant ProfessorGovt Medical College

Kottayam

05/02/2023 [email protected]

Outline

General factsWhat is ovarian reserve

Why measure ovarian reserve

Measures of ovarian reserve

Uses of ovarian

reserve testsSummary


General Facts

• Women are very different to men with regard to reproductive ageing.

• A woman’s entire lifetime’s supply of eggs is present at birth and it is limited

• Decreasing ovarian reserve is inevitable with increasing age, resulting in complete infertility by age 40-50.

• Decreasing ovarian reserve has a significant negative effect on a couple’s reproductive prospects from age 37 onwards but earlier for some women.


• Folliculogenesis is a complex developmental process involving cell proliferation and differentiation in response to gonadotropins.

• At any time there is a heterogeneous population of follicles at differentdevelopmental stages within the ovaries. These stages include resting primordial follicles, preantral and early antral follicles (0.2-2.0mm) which are in most instances gonadotropin-independent, small antral follicles (1-5mm) that are gonadotropin-responsive, and larger antral follicles (> 5mm) which aregonadotropin-dependent.

• The human ovary obtains a maximum of primordial follicles at 5 months of gestational age. Thereafter, the number decreases in a biexponential fashion until menopause.



Testing is indicated in

Before ART esp women above 30Women with a history of exposure to a confirmed gonadotoxin, i.e., tobacco smoke, chemotherapy, radiation therapy.Women with a strong family history of early menopause or premature ovarian failure.Women who have had extensive ovarian surgery, i.e., cystectomy and unilateral oophorectomy.


Ovarian reserve The concept of “ovarian reserve” defines a

woman’s reproductive potential as a function of the number and quality of her remaining oocytes in an attempt to predict reproductive potential

Ovarian Reserve = quantity and quality of the ovarian follicle/oocyte pool

Wood JW 1989 Fecundity and natural fertility in humans. Oxf Rev Reprod Biol 11:61–109


Why is prediction of ovarian reserve important in clinical

practice?† To identify who have sufficient ovarian reserve to make IVF using

their own eggs† To identify women who have little or no ovarian reserve† To identify women who may be at risk of potential OHSS

† To plan better induction protocols for success and safety of ART

† To counsel women regarding their reproductive potential

• Yates et al HR 2011


Accurate/Predictive

Highly sensitive Objective Reproducible with low inter

and intra cycle variability Easily measurable Independent of other

factors Cost-effective

Predictors of ovarian performance

The Ideal Ovarian Reserve Screening Method-IDEAL BIOMARKER


Ovarian Reserve - Tests• Age, Basal FSH (1988), E2 (1995), FSH/LH (1996)• - Inhibin-B (1989)• AMH (Anti Müllerian Hormone)

Static

• Clomifene citrate test (1987)• GnRHa test (1991) (GAST)• Gn stimulation test (1994) (EFORT)

Dynamic

• Ovarian volume• Antral follicle count(functional biomarkers)• Ovarian doppler exam • Ovarian biopsy

Ultrasonography

Newer-genetic –Single nucleiotide

pleomorphisms for fsh receptors,lh receptors

A normal ovarian reserve results in the development of 8 to 10 follicles and the retrieval of a corresponding number of healthy oocytes under exogenous gonadotropin stimulation giving an

optimal livebirth rate (Fasoultotis et al., 2000).

The most promising tests to date include ultrasound assessment for antral follicle count (AFC) and the biochemical

marker, i.e. the anti-Müllerian hormone (AMH).



Age as a biological marker5 months iu : millionsMenopause: 1000450 ovulatory cycles


Age as a biological marker

Birth rate and age

Nelson et al Hum Reprod update 2013

Miscarrage rate and age

Nelson et al Hum Reprod update 2013


Biochemical

FSHBasal (days 2-3) serum FSH levels increase with aging Indirect biomarker of ovarian reserveInfluenced by Inhibin B and EstradiolFSH assays are well standardized* but.. High Inter- and Intra-cycle Variability (Low Reliability)High number of false negatives

ie ‘Normal’FSH values DOR or failure to conceive




To summarise• Day 3 FSH is an indirect measure of the

size of follicular cohort• Single elevated FSH value has a very

limited reliability• Large inter cycle variability• Wide range of intercycle variables• Simple to perform but definitely has

limitatations


ESTRADIOL • Elevated levels may predict poor response even when

the basal FSH is normal • The estradiol level is usually low (less than 50 pg/mL) on

days 2–4 of the menstrual cycle but demonstrates some cycle-to-cycle variability.

• However, an elevated value (greater than 60–80 pg/mL) in the early follicular phase can indicate reproductive aging and hastened oocyte development..

• When interpreted it should be along with basal FSH of the same cycle.


INHIBIN B• Inhibin B is a glycoprotein hormone that is

secreted primarily by preantral and antral follicles.

• The serum concentration of inhibin B decreases with the age-related decrease in the number of oocytes.

• There is significant variability in inhibin B levels between menstrual cycles.

• This marker does not reliably predict a poor response to ovarian stimulation and, thus, is not a recommended test


AMH Dimeric glycoprotein exclusively produced by the

granulosa cells of preantral (primary and secondary) and small antral follicles. reflects the pool of remaining follicles in the ovary

Also known as Müllerian-inhibiting substance (MIS) The first mention is dated to 1940, A. Jost It is also formed in females in ovaries from the 36th week

of gestation. NOT formed in FSH-dependent (antral) follicles and also

in atretic follicles.


AMH Blood Level

Very Low Less than 0.3 ng/ml

Low 0.3 - 0.6 ng/ml

Low Normal Range 0.7 - 0.9 ng/ml

Normal Over 1.0 ng/ml

High (often PCOS) Over 3.0 ng/ml

Results are calculated in ng/mL. To convert to SI units (International System of Units):The respective converting factor is [pmol/l] = 7.14 x [ng/ml]


Ovarian response based on AMH levels

AMH LEVEL ng/ml RESPONSE

> 1.3 NORMAL

>3.5 HYPER RESPONSE

≤1.26 POOR RESPONSE (≤4 oocytes) sensitivity 97%

<0.1 NO RESPONSE

Gnoth et al 2008.

05/02/2023 [email protected] and Sterility 2013


• AMH when it decreases it is a sign of• follicular reserve exhaustion. • The hormone exhibits a fairly stable expression• throughout the menstrual cycle although minor

fluctuations may be consistent with continuous non-cyclic growth of small follicles

(La Marca et al., 2004).• Therefore, measurements of its concentration are

highly reproducible (cycle to cycle consistency) (Fanchin et al., 2005).


AMH Other usesAMH in diagnosis(monitor fertility decline)Pretreatment and post treatment levels chemotheapyPrediction of ovarian function after chemotjerapyIncorporated in Guidelines of childhood cancer treatmntResearch on the best protocol of chemotherapyHuman Reprod 2015

Low inter cycle variabilityLack of standardisation


DYNAMIC TESTS

• Clomifene citrate test (CCCT,1987)• GnRHa test (1991) (GAST)

• Gn stimulation test (EFFORT,1994)(Exogenous Fsh Ovarian Response Tests)

no additional benefit to basal

FSH


Biophysical• Antral Follicle count• Ovarian volume• Ovarian blood flow


Antral Follicular Count• Predicts the quantitative aspect of ovarian

reserve• Typically by a TV US 2D scan during early

follicular phase measuring only follicles 9 mm or less in planes calculating the mean diameter

• < 6 predicts poor response• >16 predicts excessive response• Correlates with response to Gns stimulation no of

oocytes retrieved and more recently shown to be a predictor of live birth in IVF cycle. Mazeela et al 2009







Basal ovarian volume• The calculation of ovarian volume requires ovarian

measurements in three planes and the use of the formula for the volume of an ellipsoid: D1 × D2 × D3 × 0.52.

• Mean ovarian volume, the average volume calculated for both ovaries from the same individual, is the value used to assess ovarian reserve.

Ovarian volume correlates with ovarian response to stimulation, it does not predict failure to conceive

• When screening for diminished ovarian reserve with imaging, ovarian volume has limited value compared with antral follicle count .



Basal ovarian volume and blood volume


Combined Ovarian Reserve Tests

• Because no single assessment of ovarian reserve has 100% sensitivity and specificity, tests often are combined in an attempt to improve the prediction of poor outcomes

• Antimüllerian hormone and antral follicle count are the most accurate predictors.

• Because of the heterogeneity of the tests and cutpoints used in research studies, models of combined ovarian reserve tests do not significantly improve the ability to predict poor reproductive outcomes over single ovarian reserve tests

• Complicate and increase the expense of screening.• Further research is needed to determine an optimal

combination of tests. Fertil Steril 2012;98:1407–15



To sum up• AMH is follicle gatekeeper. • AMH and AFC are the best markers of

ovarian reserve, age is the best marker for oocyte quality.

• AMH may be used in assessing ferility preservation , chemotherapy ovarian surgery. AMH may be used as a biomarker in diagnosis of endocrine disorders’ autoimmune disorders


• ORT allows

pretreatment patient counseling individualization of stimulation

strategy increased cost effectiveness enhanced safety


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Dr reji's ovarian reserve testing