Svetlana Vujović1 , M. Ivović1, M. Tančić-Gajić1, L. J. Marina1, Z. Arizanović1, M. Ivanišević1, M. Barać1, J. Micić1, B. Barać1 and D. Micić1
(1)
Medical Faculty, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia
Svetlana Vujović
Email: prof.svetlana.vujovic@gmail.com
Premature ovarian insufficiency (POI) (also known as premature menopause) is a heterogeneous disorder of multifactorial origin defined as the occurrence of secondary amenorrhoea, hypergonadotropism (follicle-stimulating hormone above 40 IU/L) and hypoestrogenism (oestradiol below 50 pmol/L) in women under the age of 40 years.
Number of total follicle count during gestation decreases from seven million during the 20th week to 300,000 during puberty. In the climacterium the expected number of follicles is 1,000. A possible mechanism of the origin of premature ovarian failure can be decreased number of primordial follicles due to atresia or altered follicle maturation. The decline in the ability to repair DNA double-strand damages by homologous recombinant repair during meiosis, due to decline in repair genes BRCA1, MRE11, Rad51 and ATM, leads to the accumulation of these damages that contribute to the depletion of the ovarian reserve.
Women with POI have 5–15 % chance of spontaneous conceiving at sometime after confirming diagnosis. Therefore it is essential to find if women wish to become pregnant or not. After initiating oestroprogestagen therapy follicle growth is possible and pregnancy can happen [1].
14.1 Ovarian Reserve Test
A number of ovarian reserve tests have been designed to determine ovarian reserve and quality [2].
These include early follicular phase (day 2 or 3) blood levels of FSH, luteinizing hormone (LH), oestradiol, antimullerian hormone (AMH) and inhibin B. Total ovarian volume and follicle count can be measured by ultrasound. There are four grades of ovarian insufficiency depending on FSH levels. Levels of FSH between 10 and 15 IU/L represent and FSH over 40 IU/L represents 4th grade of the ovarian insufficiency.
14.2 Oestradiol
The first-line therapy is a trial with oestradiol replacement with close monitoring of the ovulation.
Exogenous oestrogens could act by sensitizing and differentiating granulosa cells. They downregulate FSH and LH receptors and increase response of FSH and number of LH receptors previously induced by FSH. They lower LH and prevent premature luteinizing of the follicle. The study of Taylor et al. [3] has shown that 46 % of patients ovulate at least once during the first 12 months of oestradiol therapy. Oestradiol stimulates endometrial proliferation and production of cervical mucus.
Suggested doses are twice as high as recommended doses in the menopause. Transdermal dose of oestradiol is 100–150 ug, conjugated equine oestrones 1.25 mg and oestradiol 2–4 mg orally. Micronized progesterone in a dose of 200 mg per day or medroxyprogesterone 10 mg is advised 10 days in the luteal phase.
14.3 Oestradiol and Autoimmune POI
Oestradiol decreases activated T lymphocytes and enhances autoimmune activation of effector helper T lymphocytes and macrophages. It facilitates the maturation of pathogenic autoreactive B lymphocyte cells and diminishes the production of potentially protective B cells [4].
Blumenfeld et al. [5] performed induction of ovulation with GnRH agonist, relatively high doses of gonadotrophins and small doses of glucocorticoids. The goal of this treatment is lowering the high endogenous FSH, which is ineffective in stimulating folliculogenesis and possibly ameliorating the downregulation or desensitization of diminished FSH receptors. Release of the few FSH receptors may diminish the autoimmune process and possibly lowers the levels of the activity of these antibodies. Correnblum et al. [6] suggested prednisone 4 × 25 mg 4 weeks for ovulation induction in cases with the autoimmune cause of premature ovarian insufficiency. But corticosteroid therapy is not indicated generally in clinical practice due to a risk for osteonecrosis. No prospective randomized studies have unequivocally validated the efficiency of this combination.
14.4 Ovulation Induction Protocols
The pregnancy rate depends not only on the ovarian reserve but also on the type of infertility, the cycle number and uterus characteristics [7].
Table 14.1
Protocols for ovulation induction in premature ovarian insufficiency
|
Oestroprogestogens |
Aspirin |
|
Gonadotrophins |
Nitric oxide |
|
Clomiphene citrate |
Prednisone |
|
Aromatase inhibitors |
Plasmapheresis |
|
GnRH agonists |
Pentoxifylline-tocopherol |
|
GnRH antagonists |
Apoptotic inhibitor |
|
Recombinant LH |
Sphyngosine-1-phosphate |
|
Recombinant growth hormone |
DHEA |
Natural cycle or cycle modified with oestroprogestagens represents the method of choice nowadays with 5–15 % of success resulting in pregnancy.
Loutradis et al. [8] found that low-dose human chorionic gonadotrophin in the first days of the ovarian stimulation had promising results in grade I POI.
Oocytes of women with diminished ovarian reserve are prone to a high rate of meiosis errors leading to a high rate of aneuploidy [9].
It was found that GnRH does not improve the successful ovulation induction with exogenous gonadotrophins. van Kesteren et al. [10] gave 4 weeks intranasal buserelin 1,000 ug daily or placebo, the 3-week human menopausal gonadotrophin in weekly augmented dose, but no difference in pregnancy rate was found. Gonadotrophin therapy carries a theoretical risk for exacerbating autoimmune POI.
Dehydroepiandrosterone (DHEA) is converted to oestradiol which suppresses FSH. Increasing of the testosterone production by the very early follicles stimulates androgen receptors allowing more preantral follicles to progress to more mature antral follicles [11].
In a case of failure of all mentioned protocols, some new therapeutical options can be performed.
14.5 Modern Technique for Ovulation Induction in POI
Donor oocytes can be advised to a woman with POI failing to conceive under oestroprogestogens previously and with well-prepared endometrium (Table 14.2).
Table 14.2
Other approaches to pregnancy in POI
|
Donor oocyte |
|
Embryo freezing |
|
Freezing of mature eggs |
|
Cryopreservation and tissue transplantation |
|
Vitrification |
|
In vitro activation |
Cryopreservation is freezing of tissue or cells in order to preserve for the future [12]. Methods can be slow freezing or vitrification (ultrarapid freezing).
Vitrification is a process of converting something into a glasslike solid that is free of crystal form. By adding a cryoprotectant, water can be cooled until it hardens like glass without crystal formatting. It is important because ice crystal formate can damage frozen embryo.
Ovarian tissue cryopreservation can be performed in prepubertal girls at risk for POI, and this procedure is as feasible and safe as comparable operative procedures in children [13].
Ovary transplantation can be done with fresh cortical ovarian tissue transplantation, frozen cortical ovarian transplantation or whole ovary transplantation.
In vitro activation (IVA) requires ovaries to be removed from a woman, treated outside the body, then reimplanted near the fallopian tubes. The woman is then treated with hormones to stimulate the growth of specialized structures in ovaries called follin. These women still have very tiny primordial, primary and secondary follicles and may be treatable.
PTEN is a gene that encodes for a protein involved in several critical signalling pathways inside cells including metabolism, growth and survival. It controls follicular growth. Blocking the activity of PTEN in mouse and human ovary was enough to stir dominant follicles into growth and production of mature eggs. Ovaries can be treated with substances modulating the PTEN pathway.
Hippo pathway is another pathway for ovulation induction. Cutting ovaries into pieces disrupts a growth arrest pathway called Hippo. Hippo signalling modulates the growth of many organs. In the ovary the hippo pathway appears to ensure that only a few follicles at a time are growing.
Kawamura et al. [14] removed ovaries and ovaries from their patients and fragmented them to disrupt the Hippo pathway. Drug treatment was given to stimulate the Akt signalling pathway. After grafting the ovary tissue back to the patient, they found rapid follicular growth leading to increased expression of downstream growth factors.
Adult ovaries possess rare numbers of oogonial stem cells that can stably proliferate for months and produce mature oocytes in vitro. Injection of labelled ovarian stem cells into mouse ovaries leads to differentiation of these cells into mature oocytes that are ovulated, fertilize and generate viable neonates [15].
Intraovarian environment is important for differentiation to mature normal oocytes. However, the clinical utility of these cells for treatment requires more evidence to confirm their safety, especially the effects from epigenetic changes during in vitro culture.
It is necessary to provide the optimal therapeutic regimen, individually determined for women wanting pregnancy with premature ovarian insufficiency before oocyte donor programme. Decreasing gonadotrophin levels to the physiological range before embarking on any treatment is the most important.
Multicultural, randomized placebo-controlled trials should be carried out in the future. This may standardize the treatment of women with premature ovarian insufficiency who wish to conceive and ultimately have their biological child.
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