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Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 46-51

Diminished ovarian reserve and premature ovarian failure: A review

1 Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
2 ART Centre, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication14-Oct-2016

Correspondence Address:
Rinchen Zangmo
Flat No. 133, Chandanwari Apartment, Sector 10, Plot 8, Dwarka, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2348-2907.192284

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Diminished ovarian reserve (DOR) is defined as reduced capacity of the ovaries to produce oocytes; the oocytes produced are of poorer quality leading to the formation of poor quality embryos. The most severe form of DOR can be represented as premature ovarian failure (POF). There are various reasons leading to DOR, the most important factor being increasing age, others being endometriosis and surgeries on the ovary. POF can be due to chromosomal aberrations or secondary to chemotherapy, radiotherapy, infections, or surgeries involving the ovaries. Patients with DOR may present with infertility and menstrual cycle abnormalities; patients with sudden onset POF may also present with hot flushes and vaginal dryness. There are various tests for finding out ones's ovarian reserve, the most widely used being follicle-stimulating hormone (FSH), anti-Mullerian hormone, and antral follicle count. It is important to know a patient's ovarian reserve before recruiting her for in vitro fertilization. Various modalities have been tried to improve the outcome in candidates with DOR undergoing assisted reproductive technology. This includes high-dose FSH treatment, luteinizing hormone supplementation, GnRH antagonist cycle, and use of adjuvant treatments such as estrogen priming, growth hormone, L-arginine, and dehydroepiandrosterone. Patients who are planned for chemotherapy or radiotherapy may undergo oocyte or embryo cryopreservation before the cancer treatment. To conclude, patients with DOR and POF should be provided with good counseling and emotional support.

Keywords: Assisted reproduction, infertility, ovarian reserve, premature ovarian failure

How to cite this article:
Zangmo R, Singh N, Sharma J B. Diminished ovarian reserve and premature ovarian failure: A review. IVF Lite 2016;3:46-51

How to cite this URL:
Zangmo R, Singh N, Sharma J B. Diminished ovarian reserve and premature ovarian failure: A review. IVF Lite [serial online] 2016 [cited 2022 Jan 18];3:46-51. Available from: http://www.ivflite.org/text.asp?2016/3/2/46/192284

  Introduction Top

Ovarian reserve can be defined as the quality and the quantity of the remaining follicle pool in the ovaries. [1] 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. [2],[3],[4]

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. 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. [5],[6] Nowadays, with the increase in success rates of cancer treatment in children and in young women, the incidence of POF is rapidly rising. [7],[8]

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. [9]

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. [10]

The reduction of ovarian function with aging has been widely defined in terms of progressive reduction of ovarian follicles and diminished capability to generate competent oocytes. [11],[12] Age is considered to be the main cause of reduced ovarian reserve in a woman over 40 years of age, but as it is known, a premature reduction of ovarian reserve can also occur in young age. POF can occur spontaneously which is primary POF, or can be secondary to the consequence of chemotherapy, radiation, or surgery. Primary POF is idiopathic in about 90% of cases.

Possible reasons behind POF can be principally divided into chromosomal and nonchromosomal anomalies. About 50% of women with POF with primary amenorrhoea have associated chromosomal abnormalities, [13] whereas associated chromosomal abnormalities are much less common in women with secondary amenorrhoea.

Causes of POF other than chromosomal abnormalities are iatrogenic causes such as surgery, chemotherapy, and radiations, 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. [13] Certain gynecological conditions contributing to infertility per se may also be independently responsible for DOR. Surgeries such as endometriotic cystectomy with the use of electrosurgery and laparoscopic ovarian drilling for polycystic ovarian syndrome may inadvertently damage the normal ovarian tissue and result in DOR. [32],[38]

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. [14] 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. [15]

The risk and prevalence of idiopathic POF vary with ethnicity. Caucasian, African-American, and Hispanic women have been observed to be at a significantly augmented risk of developing idiopathic POF compared to Japanese women. [6] 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. [16]

  Diagnosis and evaluation Top

Most of the women with DOR have normal menstruation at the time of diagnosis. Some women may present with failure of restarting normal menses after pregnancy or after stopping oral contraceptives. Some patients are incidentally detected to have DOR during evaluation for infertility.

Primary POF typically presents with secondary amenorrhea or oligomenorrhea in a young woman less than 40 years of age. [17] 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; [18] on the contrary, patients with iatrogenic POF, due to surgery or cancer therapy are frequently symptomatic. The criteria to make a diagnosis of POF are not always standardized. [19] Many clinicians make the diagnosis 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. [20]

Further specific investigations to understand the cause are required, once the diagnosis has been established. Karyotyping is done to exclude genetic causes. If genetic abnormalities are identified, implications for future pregnancies should be discussed. Autoantibody screening for antiovarian, antithyroid, and antiadrenal antibodies may be advised.

The assessment of ovarian reserve has an important role in the management of patients with infertility. Clinically, the patient's age and menstrual cycle pattern give a fair idea about the patient's ovarian reserve. The follicular phase of menstrual cycle of an individual shortens with increasing age, resulting in overall shortening of the menstrual cycle length (MCL) due to reduced production of inhibin-B by the depleting follicle numbers, and subsequent premature rise of FSH production. [21],[22] According to a study, an association was found between MCL and the antral follicle count (AFC) during ultrasonographic evaluation. [23] 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. [23]

  Tests for detecting ovarian reserve Top

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. [24] Day 2-3 levels of FSH and luteinizing hormone (LH) are the most widely used test for ovarian screening.[25] Accuracy in predicting poor response is adequate only when high threshold values are used. [26] FSH should be measured various occasions to rule out discontinuous ovarian activity as a cause of increased gonadotropins. [27]

However, only increased FSH is of limited utility as far as assessment of ovarian reserve is concerned for the management of infertility. [28]

AFC is very effective in estimating the response to ovarian stimulation. [29] 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. [30],[31] 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. [32]

Another endocrine marker, inhibin B, has been identified as growth index of small antral follicle cohort. [33] Inhibins are glycoproteins produced by the granulosa and theca cells of the ovary and belong to the superfamily of transforming growth factors-β (TGFs-β). [32] Role of inhibin includes suppression of FSH production from the pituitary. [34],[35],[36] Levels of inhibit B vary with exogeneous GnRH or FSH stimulation and also between menstrual cycles. Levels are lower (<45 pg/ml) in women who are poor responders. Women with reduced ovarian reserve have reduced values of estradiol (E2) up to 50 pg/ml. [37] 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.

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). [38] 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.

  Managing a patient with diminished ovarian reserve Top

It is a challenge for infertility experts to manage a patient with DOR. The only method of achieving pregnancy in these patients is by means of assisted reproductive technique although studies have tried ovulation induction after dehydroepiandrosterone (DHEA) treatment in such patients. Women with DOR usually have less number of oocytes during oocyte retrieval; hence, fewer embryos for transfer and lesser chances of conception when compared with a woman having normal ovarian reserve. These are the women who may need cancellation of IVF cycle midway either due to the absence of follicular development or due to lack of oocytes retrieved. [39],[40],[41],[42]

The protocols that have been tried for treatment of these patients include stimulation with high doses of gonadotropins, natural cycle IVF, and minimal stimulation IVF. Several studies have also suggested a benefit of supplementation with DHEA, growth hormone, and estradiol. Cryopreservation of oocytes has come up as an important measure to preserve fertility in patients at high risk of developing POF who are not planning immediate conception. Women with severely DOR benefit best by donor oocyte program. [43]

Use of daily dose of gonadotropins, even higher than 450 IU failed to significantly improve ovarian response and clinical outcome according to various studies. [44] 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. [45]

Natural cycle IVF is a relatively easy procedure that minimizes physical and emotional stress, the costs of treatment, and laboratory tests. [46] It allows for natural selection of good quality oocytes, an improved embryo quality, [47] and a higher endometrium receptivity. [48] However, the use of natural cycles is associated with some drawbacks mainly due to the frequent spontaneous LH surge, resulting in high cancellation rate (up to 30%), difficulties in programing oocytes retrievals, high incidence of failure to recover oocytes (16.7-71.4%), and low pregnancy rate per embryo transfer (ET) cycle (0-23.5%). [49] Hence, natural cycles should not be used as the treatment of choice in patients with DOR but should be regarded as an option after repeated poor response with classical protocols of stimulation. [50]

The use of microdose flare protocol was evaluated in several retrospective studies, and it was found that this protocol results in a nonsignificant increase in delivery rate as compared to other protocols. Prospective randomized studies on larger scale are required to strengthen the use of this protocol in poor responders. [51]

The use of GnRH antagonists in the mid-late follicular phase during ovarian stimulation prevents the premature LH surge, whereas not causing suppression in the early follicular phase. [52] With this regimen, it is possible to obtain a 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. No significant improvements in the reproductive outcome were reported according to two prospective studies. [53],[54] Another prospective randomized study compared the antagonist protocol with the flare-up protocol, and it reported better results with the latter protocol. [55] D'Amato et al. retrieved a significantly higher number of oocytes and observed a significantly lower cancellation rate using GnRH antagonists in combination with clomiphene citrate and gonadotropins in a prospective study. [56]

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.

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. [57]

Adjuvant treatments, which have been tried, include estrogen priming, L-arginine, growth hormone, and DHEA supplementation.

In their retrospective study on 155 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 with failed cycle. [58]

A prospective study showed that oral L-arginine supplementation might improve ovarian response, endometrial receptivity, and pregnancy rate in poor responders. [59]

A systemic review and meta-analysis reviewed 6 randomized controlled trials with a total of 169 patients; 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. [60]

The role of DHEA in improving ovarian reserve and IVF outcomes in poor responders has been evaluated in several centers across the world including India.

A prospective study by Singh et al. found that DHEA improved all markers of ovarian reserve. [61] Another prospective study done in India on 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. [62]

Overall, there is insufficient data to support a beneficial role of DHEA as an adjuvant to controlled ovarian stimulation in IVF cycle. Only three controlled studies were eligible for a meta-analysis with 200 IVF cycles in which the researchers found that the number of oocytes retrieved was significantly lower in DHEA group. [63] Thus, well-designed, randomized controlled trials on a larger number of candidates are needed to support the use of DHEA in standard practice for poor responders.

  Conclusion Top

To conclude, it is always wise to predict the patients likely to have a compromised ovarian reserve and provide proper counseling about the available options. A heartwarming emotional support by the treating doctor provides miraculous psychological benefit to the patients.

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Conflicts of interest

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Dr. Rinchen Zangmo has done her MBBS from Government Medical College, Srinagar, She obtained the degree of M.D. Obstetrics and Gynecology from All India Institute of Medical Sciences, New Delhi, in the year June 2013. She is also a Diplomate of National Board (DNB) in Obstetrics and Gynecology.

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