Diminished Ovarian Reserve

Ovarian reserve can be defined as the quality and the quantity of the remaining follicle pool in the ovaries.  Diminished ovarian reserve (DOR) is defined as reduced capacity of the ovaries to produce oocytes. The oocytes produced by a woman with DOR are usually of poorer quality as compared to those produced by females with good ovarian reserve. The development of DOR generally reflects the process of follicular depletion and decline in oocyte quality. 
Detecting this condition before initiating an in vitro fertilization (IVF) cycle is also often helpful in characterizing women at risk of poor performance in assisted reproductive techniques. The most severe form of DOR is represented by premature ovarian failure (POF) in young females.

All we need to know & memorize about DOF (Dwindling Ovarian function and later established POF : DOR : Its defn, diag and ways and means of achieving  fertility with her own egg.

Point 1: Prevalence of POF?? Spontaneous onset POF affects 1% of women under 40 years, 0.1% of patients younger than 30 years, and 0.01% of patients under the age of 20 years.  Nowadays, with the increase in success rates of cancer treatment in children and in young women, the incidence of POF is rapidly rising.

 Point 2: Decline in no of growing follicles : Every woman behaves differently : In many situations, women of the same age are different with response to ovarian stimulation and some of young women under age 35 have a DOR and poor IVF outcome. A useful predictor of ovarian response to ovulation induction is thus needed. 



Point 3: Age of the female is the one of the most important factors in determining the quality and quantity of oocytes produced in a stimulated cycle, also an important predictor of pregnancy outcome. As a woman grows older, her ovarian reserve and her ability to conceive decrease both in natural cycle and assisted reproductive techniques cycle. 
Point 4 : Cause of POF?? Primary POF is idiopathic in about 90% of cases.
Possible reasons behind POF can be principally divided into A) chromosomal and B) nonchromosomal anomalies. About 50% of women with POF with primary amenorrhoea have associated chromosomal abnormalities,  whereas associated chromosomal abnormalities are much less common in women with secondary amenorrhoea. Autoimmune diseases, infective causes such as herpes virus, cytomegalovirus, mumps, and idiopathic. It is estimated that the 2-8% of women with mumps oophoritis develop a commonly transitory ovarian failure. Cigarette smoking was observed to be associated with an augmented risk of idiopathic POF, whereas oral contraceptive use was found to reduce the risk of early menopause in a study.



Point 5 : How   autoimmune disorders     affect  the process of  POF ? Ans: The relationship between POF and autoimmune disorders is well documented. POF is an associated occurrence in about 25% of cases of hypothyroidism, in 3% of Addison's disease, and in 2.5% of diabetes mellitus.  POF it is also associated with autoimmune polyendocrine syndromes types 1 and 2, pernicious anemia, systemic lupus erythematosus, rheumatoid arthritis, and vitiligo. Around 50% of patients with POF have ovarian antibodies, but their clinical relevance is not well defined due to their high prevalence (31%) in women with normal ovarian reserve. 


DOR: What may be the Clinical Features??  1) Many cases pass undiagnosed and some patients are incidentally detected to have DOR during evaluation for infertility. Some women may present with failure of restarting normal menses after pregnancy or after stopping oral contraceptives. Primary POF typically presents with secondary amenorrhea or oligomenorrhea in a young woman less than 40 years of age.

Words of Caution ::   In the few women who experience primary amenorrhea, there is frequently an underlying chromosomal abnormality. Women with a diagnosis of POF before of 20 years of age are considerably less likely to present with symptoms of flushing and sweats, depressive mood, and vaginal dryness;  on the contrary, patients with iatrogenic POF, due to surgery or cancer therapy are frequently symptomatic. The follicular phase of menstrual cycle of an individual shortens with increasing age, resulting in overall shortening of the menstrual cycle length due to reduced production of inhibin-B by the depleting follicle numbers, and subsequent premature rise of FSH production.  According to a study, an association was found between menstrual cycle length and the antral follicle count (AFC) during ultrasonographic evaluation. The study also found that the possibility of pregnancy with assisted reproduction was approximately doubled for women with an MCL <34 days compared with women with an MCL <26 days. 
 

Many clinicians  confirm the diag  on the basis of the presence of amenorrhea for 3-6 months, the finding of follicle-stimulating hormone (FSH) values above 40 mIU/ml on at least two different occasions, and low estrogen levels.(say < 20 pg/ml) .Karyotyping is done to exclude genetic causes.

Diagnosis :  How to confirm ?? There are five biomarkers namely basal FSH, AFC, AMH :

  E2, Inhibin B.

No 1 :-Basal FSH is a good predictor of the size of the remaining follicles pool. Elevated basal FSH levels are indicative of DOR, and women with increased basal FSH levels frequently have decreased oocytes retrieved in IVF program.  A day 2-3 levels of FSH and luteinizing hormone (LH) are the most widely used test for ovarian screening.  Accuracy in predicting poor response is adequate only when high threshold values are used.  FSH should be measured various occasions to rule out discontinuous ovarian activity as a cause of increased gonadotropins. 



No  2 : AFC is very effective in estimating the response to ovarian stimulation.  Ovarian antral follicles are evaluated by transvaginal ultrasound at the beginning of the follicular phase of menstrual cycle between day 2 and day 5 of periods. Follicles measuring 2-10 mm in size in both the ovaries represent the AFC.  AFC provides a useful assessment of ovarian reserve to predict ovarian response, estimate risk of cycle cancellation, and optimize protocol selection and also to select suitable candidate for IVF. Those gynaecologists who have their USG achieve should ideally practice this method .A week training will suffice to train himself/ herself but god machine is key to achieve reproducible results.

 Point 3: Anti-Mullerian hormone (AMH) is another marker of ovarian reserve. It is a peptide growth factor and member of TGF-β family produced by granulosa cells of preantral and small astral follicles. It functions primarily as an autocrine and paracrine regulator of follicular development. Levels of AMH are gonadotropin-independent and exhibit little variation within and between menstrual cycles. AMH inhibits recruitment of follicles from the primordial pool by modifying the FSH sensitivity of these follicles. It is reflective of the non-FSH dependent growth and has been suggested as a single best predictor of poor response to assisted reproductive technology (ART).  AMH value between 2 and 6 ng/ml is usually considered normal according to most of the laboratories. Values below 2 ng/ml are indicative of DOR. Provocative tests such as clomiphene citrate challenge test are no longer used as a means of detecting ovarian reserve in an individual.

Point  4:   serum E2 :-Women with reduced ovarian reserve have reduced values of estradiol (E2) up to 50 pg/ml, usually less than 20 pg/ml .  When measured along with basal FSH, increased day 3 estradiol reflects a poor response to ovarian stimulation. Early elevation of estradiol reflects the advanced follicular development and early selection of dominant follicle.  Estradiol should never be used alone as a biomarker for detecting ovarian reserve.

Point 5: inhibin B :   Another endocrine marker, is inhibin B, has been identified as growth index of small antral follicle cohort. . Levels are lower (<45 pg/ml) in women who are poor responders.

What special tests ??  If genetic abnormalities are identified, implications for future pregnancies should be discussed. Autoantibody screening for antiovarian, antithyroid, and antiadrenal antibodies may be advised but is of little clinical  significance unless her symp  so demands..

What protocol and starting dose of FSH if an attempt is made for her own egg-not donor egg??  Choice of gonadotrophins?? Ans: Use of daily dose of gonadotropins, even higher than 450 IU failed to significantly improve ovarian response and clinical outcome according to various studies.  A study published in the journal of human reproduction showed that use of recombinant FSH (rFSH) over highly purified gonadotropins results in significant improvement in the mean number of mature oocytes, mean peak estradiol concentration, and also a significant improvement in fertilization rates. 

Choice of Protocol?? How useful is the use of GnRH antagonists in the mid-late follicular phase during ovarian stimulation? This method  prevents the premature LH surge, whereas not causing suppression in the early follicular phase.  With this regimen, it is possible to have  more natural follicular recruitment without any inhibitory effect which can possibly be induced by the GnRH agonist. Several authors have therefore suggested the use of this protocol suitable for poor responders. Due to these conflicting results, larger controlled prospective randomized trials on GnRH antagonists are needed to assess whether GnRH antagonist protocol is truly efficacious in poor responders.

Suppl-1 : Use of recombinant LH (rLH Debatable benefit of improving IVF success by use of recombinant LH (rLH) was also studied, and available evidence does not support the addition of rLH in poor responders treated with rFSH and GnRH antagonists for IVF

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Suppl-2 : Ostrogen suppl in ART cycles :--In  poor responders, Chang et al. found that estrogen priming through luteal phase and stimulation phase improved ovarian responsiveness, and this may lead to an increase in pregnancy rate in poor responders who faced with failed cycle earlier . 

Suppl-3 : L Arginine may improve Endometrial blood supply and PR (preg Rate) in ART : A prospective study showed that oral L-arginine supplementation might improve ovarian response, endometrial receptivity, and pregnancy rate in poor responders. 

Suppl-4 GH :  How relevant is suppl of growth hormone in ART settings??  A systemic review and meta-analysis reviewed wherein, it was found that growth hormone supplementation was associated with increased clinical pregnancy rate and live birth rate in poor responders in ART cycles although analysis with a larger number of patients is required to come to a definite conclusion. 
Suppl-5 .Role of DHEA: DHEA improved all markers of ovarian reserve. The  effect of DHEA on oocytes and embryos showed that 4 months of treatment with DHEA resulted in a significant improvement in the number of oocytes retrieved, oocytes fertilized, and Grade-I embryos. The study concluded that DHEA could help improve pregnancy rate in poor responders with a history of previous failed IVF cycles.