Q.1: Definition of Dwindling Ovarian Function
(DOR=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.. Primary POF typically presents with secondary amenorrhea
or oligomenorrhea in a young woman less than 40 years of age. The
development of DOR generally reflects the process of follicular depletion and
decline in oocyte quality
Q.2: What are the possible causes?? In a given case it may be difficult to substantiate
a definite cause. There are various
reasons leading to DOR, the most important factor being A) increasing age,
others being endometriosis and surgeries on the ovary. POF can be due to
chromosomal aberrations or B) Genetic C) infections-mumps, CMV infections D) surgeries
involving the ovaries E) secondary to chemotherapy, radiotherapy) F) Cigarette smoking G) genital koch’s 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. 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. Is DOR or early depletion
of oocyte is due to an autoimmune phenomenon?? Ans: Possibly in some cases
Q.3: What may be the associated diseases?? .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 .Graves diseases. 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.
Q.4: What
are the symtomatology?? Patients with DOR may present with infertility and menstrual
cycle abnormalities ;Paradoxically many a 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
Q5: How to confirm the diag of DOR?? There are various tests for finding out ovarian reserve, like
1) follicle-stimulating hormone (FSH), 2) anti-Mullerian hormone, and 3) antral follicle count. We are aware of the
fact that it is important to know a patient's ovarian reserve before recruiting
her for in vitro fertilization.
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 programme. . If she is having periods of her own then Day 2-3 levels of FSH and luteinizing hormone (LH) are the most widely used test for ovarian reserve screening tets used followed by AMH, AFC and Serum E2 I that order. 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.
What about AFC?? 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. .
What about another Anti-Mullerian hormone (AMH) ?? 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.
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 programme. . If she is having periods of her own then Day 2-3 levels of FSH and luteinizing hormone (LH) are the most widely used test for ovarian reserve screening tets used followed by AMH, AFC and Serum E2 I that order. 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.
What about AFC?? 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. .
What about another Anti-Mullerian hormone (AMH) ?? 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.
Q. What about another uncommon rarely done in clinical practice endocrine
marker, inhibin B??, Inhibin-B has been identified as growth index
of small antral follicle cohort. 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). Role of inhibin includes suppression
of FSH production from the pituitary. 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.
Q. What about serum E2
?? Women with reduced ovarian reserve have
reduced values of estradiol (E2) up to 50 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. But a gentle caution. Estradiol
should never be used alone as a biomarker for detecting ovarian reserve.
Q Modes of Prevention: 1) Early child bearing preferably by 30yrs, to avoid smoking, lifestyle change, avoiding viral and reproductive tract infections. Cryopreservation of oocytes has come up as an important measure to preserve fertility in patients who are at high risk of developing POF who are not planning immediate conception. Women with severely DOR benefit best by donor oocyte program and it is up to the couple to accept or not.
Q Modes of Prevention: 1) Early child bearing preferably by 30yrs, to avoid smoking, lifestyle change, avoiding viral and reproductive tract infections. Cryopreservation of oocytes has come up as an important measure to preserve fertility in patients who are at high risk of developing POF who are not planning immediate conception. Women with severely DOR benefit best by donor oocyte program and it is up to the couple to accept or not.
What investigations for
POFprior to planning ART programme??
Can women with impending POF (DF) have successful in ART program or they should be outright declared for donor oocyte programme. It s difficult to answer,. But by and large ART specialists try hard at least for 1-2 cycles with her own egg by various supportive modalities like A) DHEAS ( dehydroepiandrosterone) B) CO Q C) Lycopene D) 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,. Patients who are planned for chemotherapy or radiotherapy may undergo oocyte or embryo cryopreservation before the cancer treatment.
Can women with impending POF (DF) have successful in ART program or they should be outright declared for donor oocyte programme. It s difficult to answer,. But by and large ART specialists try hard at least for 1-2 cycles with her own egg by various supportive modalities like A) DHEAS ( dehydroepiandrosterone) B) CO Q C) Lycopene D) 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,. Patients who are planned for chemotherapy or radiotherapy may undergo oocyte or embryo cryopreservation before the cancer treatment.
What about natural cycle IFV?? Ans: Natural cycle IVF is a relatively easy procedure that minimizes physical and emotional stress, the costs of treatment, and laboratory tests. It allows for natural selection of good quality oocytes, an improved embryo quality, and an optimum endometrium receptivity is expected . 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 programming oocytes retrievals, high incidence of failure to recover oocytes and low pregnancy rate per embryo transfer (ET) cycle (0-23.5%). Hence, natural cycles should not usually 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.
What about microdose flare protocol?? Ans: This was evaluated by researchers. and it was found that this protocol results in a mild increase in delivery rate as compared to other protocols.
What about Antagonist protocol?? The use of GnRH antagonists in the mid-late follicular phase during ovarian stimulation prevents the premature LH surge, . This is often used in IUI protocol too to prevent LH surge. 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. But , till date no definitive improvements in the reproductive outcome were reported .. Some study claimed that the antagonist protocol with the flare-up protocol, yield better results with the latter protocol. Some researchers have used GnRH antagonists in combination with clomiphene citrate and gonadotropins in with varying results.
By and large controlled prospective randomized trials on GnRH antagonists are needed to substatiate which may be truly efficacious in poor respond
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