Poor Ovarian Reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure (aka primary ovarian insufficiency) may represent a continuum of premature ovarian senescence.[rx] It is usually accompanied by high FSH (follicle-stimulating hormone) levels.

Types of Poor Ovarian Reserve

  • Premature ovarian failure – Defined as no menses for six months before the age of forty due to any cause. Often diagnosed by elevated gonadotropin (Follicle-stimulating hormone (FSH) and LH) levels. In some cases (more so in younger women) ovarian function and ovulation can spontaneously resume. With POF up to 50% of women may ovulate once in any given year and 5–10% may become pregnant. POF is often associated with autoimmune diseases.
  • Premature menopause – A outdated synonym for premature ovarian failure. The term encompasses premature menopause due to any cause, including surgical removal of the ovaries for any reason. Early menopause and premature ovarian failure are no longer considered to be the same condition

Causes of Poor Ovarian Reserve

The main causes of diminished ovarian reserve are:

  • Cigarette smoking.
  • Genetic abnormalities (Fragile X and other X chromosome abnormalities).
  • Aggressive treatments (radiation for cancer).
  • Ovarian surgery, such as for endometriosis.
  • Idiopathic (this means that there is no apparent cause).
  • Natural decline of the ovarian reserve due to age.[rx]
  • Genetic factors, such as fragile x syndrome. Approximately 20–28% of women with an FMR1 premutation (55–200 CGG repeats) experience fragile x primary ovarian insufficiency (POI) and another 23% experience early menopause (i.e., menopause before the age of forty-five).[rx]
  • Autoimmune disorders.
  • Adrenal gland impairment.
  • Idiopathic
  • Chemotherapy
  • Radiotherapy
  • Genetic mutations like FMR
  • Smoking
  • Ovarian surgeries
  • Autoimmune
  • Mumps
  • Galactosemia
  • Tubal surgery
  • Iatrogenic, e.g., due to radiation, chemotherapy or surgery, such as lateralization of the surface of the ovary to treat endometriosis. Excessive laparoscopic ovarian drilling has been reported to cause premature ovarian failure.[rx] (The primordial follicles are located in the thin outer one-millimeter layer of the ovary.)[rx]

Symptoms of Poor Ovarian Reserve

There aren’t many noticeable symptoms of diminished ovarian reserve. However, those with the condition might experience any of the following symptoms:

  • difficulty getting pregnant
  • late or absent menstrual periods
  • shorter menstrual cycles than average, with the average being 28 days
  • heavy menstrual flow
  • miscarriage

That said, these symptoms aren’t always present. This is why it’s important to talk to your doctor if you’re having difficulty conceiving.

Diagnosis of Poor Ovarian Reserve

  • Anti-Müllerian Hormone – Anti-Müllerian hormone (AMH), also referred to as Müllerian-inhibiting substance, is a glycoprotein hormone of the TGF-β superfamily expressed by granulosa cells as soon as the primordial follicles are recruited []; its expression is maintained until the follicles reach about 6 mm in diameter, when preantral/initial antral follicles are selected for dominance [] and follicular growth follows controlled by FSH action [].
  • Basal follicle stimulating hormone – Basal follicle stimulating hormone (FSH) levels measured on day 3 of the menstrual cycle is the most widely used ORT to assess the ovarian response to stimulation, for over two decades now.[] An increase in FSH levels occurs due to follicle depletion. The measurement of FSH is easy, and inexpensive. However, it is known to have diurnal, intra- and intercycle variability.[,] There is no universally accepted cut-off value to identify a poor response. A wide range in threshold values up to 25 IU/L has been used to define abnormal levels of basal FSH.
  • Anti-Mullerian hormone – Anti-Mullerian hormone (AMH) is a dimeric glycoprotein exclusively produced by granulosa cells of preantral (primary and secondary) and small antral follicles (AFs) in the ovary. The production of AMH starts following follicular transition from the primordial to the primary stage, and it continues until the follicles reach the antral stages, with diameters of 2-6 mm.[–]
  • Inhibin B – Inhibin B is a heterodimeric glycoprotein released by the granulosa cells of the follicle. Women with a low day 3 inhibin B concentration (<45 pg/ml) have a poor response to superovulation for IVF and are less likely to conceive a clinical pregnancy.[] It is also noted that a decrease in inhibin B probably precedes the increase in the FSH concentration.[] However, other investigators have failed to show any added predictive value for inhibin B as a measure of ovarian reserve[,] and nonoccurrence of pregnancy.[] At very low threshold levels, the accuracy in the prediction of a poor response and nonpregnancy is only modest[] and hence its routine use cannot be recommended. An exaggerated inhibin B response to exogenous FSH ORT has been found to be a predictor of hyper-response in a subsequent cycle.[]
  • Basal estradiol – Basal estradiol (E2) has been evaluated as a marker of ovarian reserve in women, prior to IVF. An elevated basal E2 level may mask abnormal FSH levels and hence, FSH levels alone may not be predictable of the ovarian response in such women. Initial studies did show an association between an elevated basal E2 level and a poor ovarian response,[–] using different values to define elevated estradiol. A large study showed that a poor ovarian response was more commonly seen in those with <20 or >80 pg/ml of estradiol but did not show any correlation to the pregnancy rate.[]
  • Clomiphene citrate challenge test – Clomiphene citrate challenge test (CCCT) is a dynamic test involving the administration of 100 mg of clomiphene citrate from the fifth day of the cycle for 5 days. Basal FSH is estimated on day 3 of the cycle and stimulated FSH levels on day 10. Abnormal values on day 3 or day 10, or on addition of the two, is considered as a predictor of a poor ovarian response. However, a meta-analysis has shown that CCCT is no better than basal FSH in predicting a clinical pregnancy.[] []
  • Exogenous follicle stimulating hormone ovarian reserve test – This dynamic test involves the measurement of basal FSH and estradiol followed by the administration of 300 IU FSH on day 3 of the cycle. The serum estradiol concentration is determined 24 h later. It is found to be better than CCCT in predicting hyper-responders and inferior to the latter in predicting a poor response. But, in view of the high rate of false positives, the authors did not recommend this test alone for the identification of hyper-responders.[]
  • Gonadotrophin releasing hormone agonist stimulation test – It involves the assessment of serum estradiol on day 2 of the cycle followed by the subcutaneous administration of GnRHa (Triptorelin) 100 μg. A change in estradiol levels is noted by repeating the test 24 h later on day 3. A rise in estradiol is considered to be indicative of good ovarian reserve. It is found to have a good ability for the prediction of poor ovarian reserve but is not superior to inhibin B or AFC in this regard.[]
  • Antral follicle count – AFs are measured by transvaginal ultrasonography in the early follicular phase, by taking the mean of two perpendicular measurements. The numbers of follicles in both ovaries are added for the total AFC. AFC has long been used as a marker of ovarian reserve.[,] A count of 8–10 is considered as a predictor of a normal response. Different diameters are used to define AFs – those measuring 2–6 and 7–10 mm. []
  • Ovarian volume – The ovarian volume is measured by transvaginal ultrasonography applying the formula for an ellipsoid (D1 × D2 × D3 × π/6). The volume of each ovary is calculated by measuring in three perpendicular directions. The volumes of both ovaries are added for the total basal ovarian volume (BOV). The ovarian volume remains unchanged till the perimenopausal period and does not add to the predictive value of AFC.[,] A decline in the ovarian volume is a late event noticed in women >40 years.[]
  • Ovarian vascularity – The observation of the ovarian Doppler flow during ovarian stimulation has been studied in IVF cycles. The increase in the Doppler flow noted during stimulation is considered not to provide additional information to AFC.[]
  • Ovarian biopsy – Ovarian biopsy done at laparoscopy or laparotomy has shown that the follicular density reduces with age and is correlated with the ovarian volume in women >35 years of age.[] Also, women with unexplained infertility have fewer follicles than those with tubal factor infertility. However, the distribution of follicles is not uniform within the ovary and hence the biopsy may not represent the true follicular density.[] It is understood that an invasive ovarian biopsy does not add to the information available through noninvasive modalities and it is not recommended to be used as an ORT.[]
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Treatment of Poor Ovarian Reserve

Variable success rate with treatment, very few controlled studies, mostly case reports. Treatment success strongly tends to diminish with age and degree of elevation of FSH.

  • Donor oocyte – Oocyte donation is the most successful method for producing pregnancy in perimenopausal women. In the UK the use of donor oocytes after natural menopause is controversial.[rx] A 1995 study reported that women age fifty or higher experience similar pregnancy rates after oocyte donation as younger women. They are at equal risk for multiple gestations as younger women. In addition, antenatal complications were experienced by the majority of patients, and that high-risk obstetric surveillance and care is vital.[rx]
  • Natural or Mini-IVF – but without the use of hCG to trigger ovulation, instead the GnRH agonist Synarel (nafarelin acetate) in a diluted form is taken as a nasal spray to trigger ovulation. Human chorionic gonadotropin (hCG) has a long half-life and may stimulate (luteinize) small follicles prematurely and cause them to become cysts. Whereas nafarelin acetate in a nasal spray induces a short-lived LH surge that is high enough to induce ovulation in large follicles, but too short-lived to adversely affect small follicles. This increases the likelihood of the small follicles and oocytes therein developing normally for upcoming cycles and also allows the woman to cycle without taking a break and consequently increases the probability of conception in poor ovarian reserve women and advanced reproductive-aged women.[rx]
  • Pretreatment with 50 mcg ethinylestradiol –  three times a day for two weeks, followed by recombinant FSH 200 IU/day subcutaneously. Ethinylestradiol treatment was maintained during FSH stimulation. When at least one follicle reached 18mm in diameter and serum estradiol was greater or equal to 150 pg/ML ovulation was induced with an intramuscular injection of 10,000 IU of hCG (human chorionic gonadotropin hormone). For luteal phase support, 5,000 IU of hCG was administered every 72 hours. Out of 25 patients, 8 ovulated and 4 became pregnant. In the control group, there were no ovulation. The patients ranged in age between 24 and 39 years with an average age of 32.7. All women had amenorrhea for at least 6 months (average 16.75 months) and FSH levels greater or equal than 40 mIU/mL (average FSH 68 mIU/ML). The researchers believe this protocol would work for women in early postmenopause as well.[rx]
  • Ethinylestradiol or other synthetic estrogens – along with luteal phase progesterone (twice daily 200 mg vaginal suppositories) and estradiol support. Ethinylestradiol lowers high FSH levels which then, it is theorized, up-regulates FSH receptor sites and restores sensitivity to FSH. Ethinylestradiol also has the advantage that it does not interfere with the measurement of serum levels of endogenous estradiol. During the luteal phase, the FSH levels should be kept low for subsequent cycles, thus the phase is supplemented with 4 mg[rx] oral estradiol. Since conception may have occurred estradiol is used instead of synthetic ethinylestradiol.[rx]
  • Cyclical hormone replacement therapy.[rx]
  • The following protocols have shown promise – high dose gonadotropins, flare-up GnRH-a protocol (standard or microdose), stop protocols, short protocol, natural cycle or modified natural cycle and low dose hCG during the beginning of the stimulation protocol.[rx]
  • Gonadotropin-releasing hormone agonist/antagonist – conversion with estrogen priming (AACEP) protocol. Fisch, Keskintepe, and Sher report 35% (14 out of 40) ongoing gestation in women with elevated FSH levels (all women had prior IVF and poor quality embryos); among women aged 41–42, the ongoing gestation rate was 19% (5 out of 26).[rx]
  • DHEA – Recent clinical trial by the Center for Human Reproduction in New York showed significant effectiveness.[rx][rx] Leonidas and Eudoxia Mamas report six cases of premature ovarian failure. After two to six months of treatment with DHEA (Two 25 mg capsules daily in five cases and three 25 mg capsules daily in one case.), all women conceived. One delivered via C-section, one aborted at 7 weeks and the remaining four were reported at 11 to 27 weeks gestation. Ages were from 37 to 40. FSH levels were from 30 to 112 mIU/mL. Amenorrhea ranged from 9 to 13 months.[rx] In addition, there is strong evidence that continuous micronized DHEA 25 mg TID reduces miscarriage and aneuploidy rates, especially above age 35.[rx]
  • Glucocorticoid therapy – A recent (2007) randomized double-blind study done in Egypt reported a statistically significant therapeutic effect with dexamethasone pretreatment. Fifty-eight women with idiopathic premature ovarian failure and normal karyotype were divided into two groups of twenty-nine. The control group received a placebo for twenty-eight days and then GnRH agonists plus gonadotropin therapy (hMG). The treatment group received dexamethasone for twenty-eight days (6 mg/ day) and then GnRH agonists plus gonadotropin therapy (hMG). (In both groups after the first twenty-eight days, and concurrent with the GnRH agonist treatment, the placebo or dexamethasone was gradually tapered off over ten days.) The treatment group had six ovulations and two pregnancies (p-value of .02). The control group had three ovulations and no pregnancies.[rx][rx]
  • A combined pentoxifylline-tocopherol – treatment has been reported effective in improving uterine parameters in women with POF undergoing IVF with donor oocytes (IVF-OD). Three women with uterine hormone resistance despite high estradiol (E2) plasma levels received treatment with 800 mg pentoxifylline and 1000 IU of vitamin E for at least nine months. Three frozen-thawed embryo transfers (ETs) resulted in two viable pregnancies. Mean endometrial thickness increased from 4.9 mm (with thin uterine crosses) to 7.4 mm with nice uterine crosses.[rx][rx] This treatment protocol has also reversed some cases of iatrogenic POF caused by full-body radiation treatment.[rx]
  • Letrozole and clomiphene citrate co-treatment – In a recent retrospective analysis of 220 poor responders, the effects of different doses of letrozole (LZ) combined with gonadotropins (Gn) and high-dose gonadotropin stimulation in antagonist cycles were compared. Patients were divided into Group 1 (LZ 5 mg for 5 days sequentially overlapping with Gn cycles), group 2 (LZ 7.5 mg for 3 days sequentially with Gn cycles), and group 3 (high-dose Gn cycles) []. The amount of gonadotropin used in letrozole groups was lower with comparable pregnancy and live birth rates between the groups [].
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  • Standard high dose gonadotropin – antagonist protocol (≥ 300 IU / day) was compared with a minimal stimulation protocol (150 IU / day) using overlapping with letrozole in antagonist cycle in poor responders, in a retrospective cohort study. The low dose protocol consisted of low dose of 2.5 mg PO over 5 days, starting from cycle day 2. On day 4 of the cycle (day 3 of the letrozole treatment) overlapping low dose gonadotropins were started. The high-dose group received high levels of gonadotropins (≥300 IU/day) starting from day 2 of their cycle and throughout their short antagonist cycle.
  • Minimal stimulation – A recent multi-center randomized non-infertility trial studied the pregnancy rates in mild ovarian stimulation strategy in women with poor ovarian reserve compared to those with conventional ovarian stimulation. Low – dose 150 IU FSH with antagonist was compared with a high dose of 450 IU HMG with long mid-luteal GnRH- agonist. The ongoing pregnancy rate in the minimal stimulation was 12.8% versus 13.6% for the conventional stimulation group. The duration of ovarian stimulation and the number of gonadotropins used was significantly lower in the former group. The study concluded that high dosages of gonadotropins are not necessary in women with poor ovarian reserve [].
  • Androgen (Dehydroepiandrosterone or testosterone) – Among the various adjuncts used to better the IVF outcome in poor responders are dehydroepiandrosterone (DHEA) and testosterone (T). DHEA and T are steroid hormones meant to increase conception rates by positively affecting follicular response to gonadotropin stimulation, in turn leading to better oocyte yield and pregnancy. Androgen also increases FSH receptor expression in granulosa cells. Cochrane Database Systematic Review in 2015 indicated that pre-treatment with DHEA led to higher live birth and ongoing pregnancy rates compared to no treatment or placebo with an odds ratio of 1.88 and 95% CI.
  • Estradiol priming in luteal phase – Estradiol priming in the luteal phase with or without the simultaneous use of GnRH antagonist was found to decrease the risk of cycle cancellation and increase the chances of clinical pregnancy in a meta-analysis of 8 studies []. Luteal estradiol priming improves follicle synchronization. However, further studies are needed to establish the role of estradiol priming.
  • Recombinant LH – Both LH and FSH are required for adequate ovarian estrogen biosynthesis and folliculogenesis. Theca cell-derived androgen production controlled by LH is necessary for estrogen production by granulosa cells. In the mid-to-late follicular phase, FSH induces LH/hCG receptor expression in granulosa cells of large follicles []. In a recent meta-analysis of 40 studies, significantly more oocytes were retrieved and significantly higher clinical pregnancy rates were observed with recombinant – human FSH plus recombinant LH versus recombinant-FSH treatment alone in poor responders, suggesting that there’s an increase in the clinical pregnancy rates of 30% in poor responders with the addition of recombinant LH.
  • Growth hormone (GH) – The use of GH is believed to modulate the action of FSH on granulose cells by up-regulating the local synthesis of Insulin-like growth factor – I (IGF -1) []. Cycle cancellation rates and a dose of gonadotropins were reduced in patients who received GH in a meta-analysis of 6 RCTs involving 169 patients []. Another meta-analysis involving 11 RCTs with 663 patients also reported significantly higher clinical pregnancy and live birth rates, oocyte yield, MII oocytes, and E2 levels on the day of human chorionic gonadotropin (HCG). These two recent meta-analyses have suggested a significant improvement in clinical pregnancy and live birth rates, oocyte yield, mature oocytes with the use of GH [, ]. Large scale multicentric double-blinded randomized controlled trials are needed to establish the efficacy and safety of GH beyond doubt in poor responders.
  • Melatonin – Melatonin, a pineal gland hormone, regulates physiologic reproductive behavior and acts as a free radical scavenger []. Melatonin supplementation has been used to improve the outcome of IVF cycles in PCOS patients and women with DOR []. The mean estradiol level on the trigger day, mature oocyte yield, and top-quality embryos were higher among women who received melatonin. However, there was no difference in other ART outcomes between melatonin and no-melatonin groups [].
  • Aspirin – Good intra-ovarian blood flow is believed to improve the delivery of gonadotropic hormones for folliculogenesis and poor ovarian blood flow is linked to poor reserve [, ]. The use of aspirin in IVF has been a topic of debate. The conclusion of a meta-analysis in 2007 was that the clinical pregnancy rate per embryo transfer did not improve with low- dose aspirin, and the use of aspirin should not be routinely recommended [].
  • Oocyte accumulation – Novel vitrification technologies are being used to accumulate oocytes from several ovarian stimulation cycles, creating a similar situation as in normorespnder. Oocyte accumulation by vitrification followed by insemination yields comparable success in low responders []. It was possible to achieve higher live birth rates per patient and reduce dropouts with oocyte accumulation in a study by Cobo, et al. [].
  • Dual stimulation/double stimulation (follicular and luteal phase) – More recent evidence suggests that folliculogenesis occurs in a wave-like fashion through the menstrual cycle and that there are multiple recruitment waves []. This has opened up a new horizon of opportunities to utilize ovarian stimulation in the luteal phase following oocyte retrieval with follicular phase stimulation in the same cycle []. Typically, a luteal phase stimulation starts 2–7 days after oocyte retrieval in the same cycle. Either Gonadotropins or CC or Letrozole are used followed by a trigger at lead follicle size of 18 mm.
  • Oocyte donation – Egg donation may be the last efficient resort to offer hope to patients with a diminished ovarian reserve and poor response. Though the pregnancy rates in women who use egg donation are at least as good as normal-responders, the decision is often difficult to make. Moreover, the facilities for egg donation, the acceptability, and adequate counseling may not be available worldwide.
  • Androgen supplementation – in the form of oral dehydroepiandrosterone or transdermal testosterone in poor responders has been explored as it is believed to improve the intrafollicular environment and follicular sensitivity to exogenous FSH. Available evidence shows a modest improvement in various parameters including a number of oocytes, embryo quality, and live birth rates.[,,,]
  • Growth hormone (GH) supplementation – is another adjuvant therapy used in combination with COS in an attempt to improve oocyte yield and pregnancy rates in poor responders. Limited evidence involving a small number of women suggests that GH as an adjuvant may be beneficial in poor responders.[]
  • Recombinant Luteinizing Hormone Supplementation – Several trials have examined the clinical utility of adding recombinant Luteinizing Hormone (rLH) in women with ovarian resistance to gonadotropin [–. In the larger ones, the ovarian resistance was identified in the form of an “initial slow response” in follicle growth , . In others, involving a lower number of cases, the hypo-response was retrospectively diagnosed in women who required higher-than-expected doses of gonadotropins considering their age, body mass index, and ovarian reserve , . Data from the more robust studies indicate that in slow responders, LH supplementation starting from stimulation days 7–10 might be more efficient than increasing the dosage of rFSH to rescue the ongoing cycle.
  • Dehydroepiandrosterone – Dehydroepiandrosterone (DHEA) supplementation before OS has been proposed to counteract the age-related fertility decline –. The last Cochrane meta-analysis including 12 RCTs concluded that pretreatment with DHEA could significantly improve the live birth rate in poor responders and in advanced age women . Two RCTs trials were conducted in women fitting Poseidon groups 2, namely those characterized by advanced age and good ovarian reserve ,
  • Double Stimulation in the Same Ovarian Cycle – A novel controlled ovarian stimulation approach has been proposed in women of low prognosis as a mean to increase the number of retrieved oocytes and the number of blastocysts available to biopsy for a preimplantation genetic test for aneuploidies (PGT-A) in a single ovarian cycle [. This method, referred to as “DuoStim,” combines the conventional follicular phase stimulation (FPS) with luteal phase stimulation (LPS). In both the FPS and LPS, patients undergo co-treatment with a maximal dose of FSH (300 IU/day) plus LH (150 IU/day) using a GnRH antagonist regimen .
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