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Lithuanian University of Health Sciences

Medical Academy

Faculty Of Medicine

Department of Obstetrics and Gynecology

Aleksandra Matwiejczyk

Premature ovarian failure and pregnancy chances

Master’s Thesis

Supervisor

PhD, dr. Sonata Barilienė

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TABLE OF CONTENT

1. SUMMARY ...3 2. CONFLICTS OF INTERESTS ...4 3. ABBREVIATIONS LIST ...4 4. INTRODUCTION ...5

5. AIM AND OBJECTIVES ...7

6. LITERATURE ...7

6.1. Definition of the POF ...7

6.2. Etiology of the POF ...7

6.3. Consequences arising from POF ... 12

6.4. Pathophysiology of the POF ... 15

6.5. Clinical presentation of the POF... 16

6.6. Diagnosis of the POF ... 17

6.7. Treatment of the POF ... 22

6.8. Pregnancy among women with POF ... 25

6.9. POF among women after oncological treatment and their pregnancy ... 28

6.10. POF among women with different race and their pregnancy outcomes... 34

7. RESEARCH METHODOLOGY AND METHODS... 37

8. RESULTS ... 39

9. DISCUSSION OF THE RESULTS ... 41

10. CONCLUSIONS ... 45

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1. SUMMRY

Aleksandra Matwiejczyk

Premature ovarian failure and pregnancy chances

Background: Premature ovarian failure (POF) is a primary ovarian defect characterized by the absence of menarche (primary amenorrhea) or premature depletion of ovarian follicles

before the age of 40 years (secondary amenorrhea). POF is a heterogeneous disorder which means that it might have a variety of causes. It is characterized by low levels of gonadal (estrogen and inhibin) hormones and high levels of gonadotropins – hypergonadotropic amenorrhea. Diagnosis is based on finding of the amenorrhea before age on 40 and associated with follicle - stimulating hormone (FSH) level in the menopausal range.

Methods: The analysis of 144 articles which were published in PubMed website was done, regarding POF and future pregnancy challenge arising from POF problem. Premature ovarian failure, pregnancy, infertility as a keywords were used.

Results: There is reduced infertility accessed and in vitro fertilization outcomes in Asian, Black and Hispanic women in comparison to White women. Clinical pregnancy rates and live birth rates is also decreased in relative to Whites. The lowest clinical pregnancy rates and live birth rates shows Asian women. Among oncological patient the highest clinical pregnancy rates and live birth rates occurs in women who decided to use of the embryo cryopreservation as a fertility preservation method. The lowest indicator is characterized with using ovarian tissue cryopreservation.

Conclusion: In vitro fertilization technique is the main option directed to patients with POF problem. Among included ethnicity, Black Women show the poorest pregnancy outcomes. Whites women represent the group with the highest pregnancy outcomes. Fertility preservation methods significantly increase pregnancy chances among women who need to undergo oncological treatment.

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2. CONFLICTS OF INTERESTS

The author reports no conflicts of interest.

3. ABBREVIATIONS LIST

ACTH - Adrenocorticotropic Hormone  AMH - Ani – Müllerian Hormone  β – HCG - Beta Chorionic Gonadotropin  3β – HSD - 3β-hydroxysteroid dehydrogenase  BP - Blood Pressure

 BMI - Body Mass Index

 BMT - Bone Marrow Transplant

 COCP – Combined Oral Contraceptive Pills  CVD - Cardiovascular Diseases

 DM - Diabetes Mellitus  ED - Egg Donation

 ESHRE - European Society of Human Reproductive Medicine  FSH - Follicle Stimulating Hormone

 GnRH - Gonadotropin Releasing Hormone  Gy - Gray

 HRT - Hormonal Replacement Therapy

 HPA - Hypothalamus – Pituitary – Adrenals Axis  IUDs - Intrauterine Devices

 IMS - International Menopause Society  IVF - In Vitro Fertilization

 LH - Luteinizing Hormone  POF - Premature Ovarian Failure  PRL – Prolactin

 RR – Relative Risk

 SART – Society of Assisted Reproductive Technology  SWAN - Study of Women’s Health Across the Nation  SLE - Systemic Lupus Erythromatous

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5  USG - Ultrasound

 USA - United States of America

4. INTRODUCTION

Primary ovarian failure (POF) is primary ovarian defect characterized by absent of menarche, what is called primary amenorrhea. POF can also be present as premature

depletion of ovarian follicles before age of 40, what is called secondary amenorrhea. It’s heterogeneous disorder affecting approximately 1% of women younger than 40 years old

(Beck-Peccoz P, Persani L.; Premature ovarian failure; Orphanet J Rare Dis. 2006 Apr 6;1:9). The most severe form of POF is characterized by lack of pubertal development due to ovarian

dysgenesis. Post-pubertal onset of primary ovarian failure is characterized by disappearance of menstrual cycles due to premature follicular depletion. Main features

of the POF are typical for physiological climacterium. Typical symptoms are: infertility, heat intolerance, flushes, anxiety, depression and fatigue. Main hallmarks of the POF are low levels of gonadal hormones: oestrogens and inhibins and high levels of gonadotropins:

(luteinizing hormone (LH) and follicle stimulating hormone (FSH). POF has a lot of important consequences for patient’s health and psychological well being. The main one

is infertility. Hormone deficiency may lead to severe neurological, metabolic and cardiovascular problems. Because POF is heterogeneous problem, then variety of causes may be possible. In majority of cases the underlying cause is not identified. The most common are autoimmunity, such as autoimmune ovarian damage, toxins and drugs. Iatrogenic causes, following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. POF is strongly related with genetic component in many cases, mainly with X chromosome abnormalities such as Turner Syndrome (Beck-Peccoz P, Persani L.; Premature ovarian failure; Orphanet J Rare Dis. 2006 Apr 6;1:9). Autosomal abnormalities have been also observed. A large number of genes have been screened as candidates for causing POF; however, few clear causal mutations have been identified (Beck-Peccoz P, Persani L.;

Premature ovarian failure; Orphanet J Rare Dis. 2006 Apr 6;1:9). The diagnosis is based on finding of amenorrhea before age 40 associated with FSH level in the menopausal range.

Screening for associated autoimmune disorders and karyotyping, particularly in early onset

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6 or ultrasound in making the diagnosis. Treatment of primary ovarian failure includes hormone

replacement therapy (HRT) and infertility management. The most common solution for infertility problem is in vitro fertilization (IVF) with donated oocytes. Embryo

cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation hold promise in cases where ovarian failureis foreseeable as in women undergoing cancer treatments.

Literature review of several publications shows increased prevalence of POF among

women in their reproductive age (Pouresmaeili F., Fazeli Z.; Premature Ovarian Failure: A Critical Condition in The Reproductive Potential with Various Genetic Causes;

International journal of fertility & sterility 8(1):1-12 ,March 2014). Nowadays more young women get cancer and need to face with oncological treatment.

Chemotherapy and radiation are top causes of POF and make desire of pregnancy a great challenge. Clinicians need to constantly train in new options and possibilities how to preserve patient’s fertility. For those women is harder to get pregnant and sometimes severity of the

malignancy doesn’t let the patient to use fertility preservation solutions. It’s always risk of cancer recurrence and due to that pregnancy may not be indicated. It makes also great

psychological issue for the couple. POF also varies by ethnicity among particular groups of women (Gold et al). It’s related to their physiology, vulnerabilities to the diseases,

environmental factors and immune system function. Particular races are more susceptible to different factors than the others such as genetic determination, ovarian aging, age of menopause and loss of ovarian follicles, environmental factors, various lifestyle. In racial

factor is very important to keep in mind culture and environment in which woman lives. Significant is socioeconomic status, education level and financial access to forms of infertility treatment. The main aim of literature review is to find out what are the possibilities for the young women with POF to achieve pregnancy considering to oncological treatment and racial factor.

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5. AIM AND OBJECTIVES

Aim of the study:

to find out what are the possibilities for the women with POF to achieve pregnancy.

Objectives:

1. To describe possibilities that can be used among cancer women to preserve their fertility,

2. To evaluate how oncological treatment influence on future pregnancy achievement among women following fertility preservation

3. To evaluate the impact of the racial factor on pregnancy and POF among women.

6. LITERATURE

6.1. Definition of the POF

Premature ovarian failure (POF) is defined by association of the amenorrhea, deficiency of sex steroidal hormones and increase levels of serum gonadotropines before age of 40 (Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr. Rev. 18, 107–134 (1997); Skillern A, Rajkovic A. Recent developments in identifying genetic determinants of premature ovarian failure. Sex. Dev. 2(4–5), 228–243 (2008); Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes. Ann. NY Acad. Sci. 1135, 146–154 (2008)).

6.2. Etiology of the POF

The total ovarian follicle complement is determined by events that occur before birth (Baker TC. A quantitative and cytological study of germ cells in human ovaries. Proc Roy

Soc 1963; 158: 417-433). Follicles initial supply that we get at the beginning in the future can be influenced by individual’s genetic. Additional insults affected the ovaries might be autoimmune, infectious, surgical, vascular or toxic. Woman’s individual factors will

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8 determine the extent to which each of those risk factors will compromise the follicle pool. POF can be considered as primary (spontaneous) or secondary (iatrogenic). The multiple etiologies of spontaneous POI that are recognized thus far include genetic, autoimmune, infectious, and idiopathic. Most cases of POI, accounting for over 90%, are idiopathic with

no discernable cause (Nelson LM: Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009; 360(6): 606–14).

1) Genetic

Genetic influences determine the size of the primordial follicle pool, impact on the rate of follicular atresia, and are a major determinant of eventual age at menopause (Qin Y, Jiao X,

Simpson JL, et al.: Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015; 21(6): 787–808). Various genetic mechanisms

implicated in the pathogenesis of POF include reduced gene dosage and non-specific

chromosome effects that impair meiosis. These can lead to ovarian failure by causing a decrease in the pool of primordial follicles, increased atresia of the ovarian follicles due to

apoptosis, or failure of follicle maturation (Premature ovarian failure; Goswami D, Conway GS, Hum Reprod Update. 2005 Jul-Aug; 11(4):391-410).

 Chromosomal Abnormalities

Any defect of the female sex chromosome - the X chromosome - can cause ovarian failure. One of the most common form is Turner Syndrome. Women with Turner's syndrome

have one X chromosome missing giving the chromosomal make-up of 45XO. They are commonly of short stature, do not spontaneously enter puberty and have characteristic

phenotypic features. The very early development of the ovary in Turner's syndrome appears

normal, but all germ cells are lost by birth, giving a picture of gonadal dysgenesis. This is most likely caused by lack of diploid dosage of one or more vital genes and accelerated

follicular atresia. It demonstrates that two intact X chromosomes are vital for normal ovarian function in this syndrome (Zinn et al 1993). From the study it is clear that at least three loci are critical for ovarian development (Powell CM, Taggart RT, Drumheller TC et al. Molecular and cytogenetic studies of an X autosome translocation in a patient with premature ovanan failure and review of the literature. Am J Med Genet 1994; 52 19-26). On a short arm of the X chromosome are genes responsible for the stigmata of Turner's syndrom and primary amenorrhea. Histological data indicate that oogenesis proceeds normally in these individuals

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until diplotene oocytes begin to be incorporated into follicles. There is a subsequent block in the production of complete follicles manifesting as follicular atresia. In 80% of cases, the paternally derived is lost (Analysis of the origin of Turner's syndrome using polymorphic

DNA probes; Loughlin SA, Redha A, McIver J, Boyd E, Carothers A, Connor JMJ Med Genet. 1991 Mar; 28(3):156-8).

In some instances POF might be familiar, may appear in several female members of the same family where no cytogenetic defect can be identified (Vegetti W, Tibilem M, Testa G et al. Inhentance in ldiopathic premature ovanan failure: analysis of 71 cases. Hum Reprod 1998; 13 1796-800). In most imstances, the mode of inheritance of ovarian failure in such families is not known and much research is directed at unravelling the genetic pattern in such pedigrees. Familial POF has several modes of inheritance - autosomal dominant, autosomal

recessive and X linked inheritance (Coulam CB, Stnngfellow S, Hoefnagel D. Evidence for a genetic factor in the aetiology of premature ovanan failure. Fertil Stertl 1983; 40: 693-5;

Mattison DR, Evans MI, Schwimmer MB, White BJ, Jensen B, Schulman JD. Familial premature ovanan failure. Am J Hum Genet 1984; 36: 1341—8).

 POF genes on the X chromosome

Fragile X syndrome is an X-linked dominant condition with incomplete penetration. It is the most common hereditary cause of mental retardation and developmental delay (Five

years of molecular diagnosis of Fragile X syndrome (1997-2001): a collaborative study reporting 95% of the activity in France. Biancalana V, Beldjord C, Taillandier A, Szpiro-Tapia S, Cusin V, Gerson F, Philippe C, Mandel JLAm J Med Genet A. 2004 Sep 1; 129A(3):218-24).

It is caused by an expansion of CGG trinucleotide repeats in the 5′ untranslated region of the

first exon of the fragile X mental retardation 1 (FMR1) gene. A recent study showed that a number of CGG repeats between 30 and 40 might be used to predict premature ovarian

aging and POF in infertile patients (The significance of the number of CGG repeats and autoantibodies in premature ovarian failure. Fiçicioglu C, Yildirim G, Attar R, Kumbak B, Yesildaglar N Reprod Biomed Online. 2010 Jun; 20(6):776-82). Some of the women with

the FMR1 gene premutation will develop POF and an increasing number of CGG repeats is associated with younger age at menopause (Schlessinger D, Herrera L, Crisponi L, et al.

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10  Autosomal disorders

Gonadotropin receptor dysfunction: Follicle stimulating hormone (FSH) and luteinizing hormone (LH) have important roles in the recruitment, development, and maturation of ovarian follicles. FSH and LH receptor genes map to 2p21. Some studies have reported inactivating mutations of the FSH or LH receptor genes in connection with

hypergonadotropic ovarian failure (Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor

gene. Latronico AC, Anasti J, Arnhold IJ, Rapaport R, Mendonca BB, Bloise W, Castro M,

Tsigos C, Chrousos GP N Engl J Med. 1996 Feb 22; 334(8):507-12). Histological studies of ovaries in patients with FSH receptor gene mutations have showed a streak or hypoplastic

gonad with impaired follicular development of the primordial and primary follicles. POF has

been identified in patients with a defect in the guanine nucleotide regulatory protein

of adenylate cyclase (G-protein), which is linked to the FSH and LH receptors as a second-messenger system (Mahbod E., Firoozeh A.; Pathogenesis and Causes of Premature Ovarian Failure: An Update; Int J Fertil Steril. 2011 Jul-Sep; 5(2): 54–65).

2) Autoimmunity

Some cases of POF may be due to an abnormal self-recognition by the immune system. Probably the genetic or environmental factors initiate the immune response. Autoimmune mechanisms are involved in the pathogenesis of 4-30% of POF cases (Bakalov VK, Anasti

JN, Calis KA, Vanderhoof VH, Premkumar A, Chen S, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46, XX spontaneous premature

ovarian failure Fertil Steril. 2005;84(4):958–965). The major histocompatibility complex antigen, cytokines, cell-mediated immunity and antibody-mediated immunity have important roles. Several autoimmune disorders have been associated with POF; hypothyroidism is the most common. Both endocrine (thyroid, hypoparathyroidism, diabetes mellitus, hypophsitis) and non-endocrine disorders (chronic candidiasis, idiophatic thrombocytopenic purpura, vitiligo, alopecia, autoimmune hemolytic anemia, pernicious anemia, SLE, rheumatoid arthritis, Crohn’s disease, Sjogren syndrome, primary billiary cirrhosis and chronic active hepatitis) were observed in association with autoimmune POF (Ashrafi M, Fallahian M,

Eshrati B, Salman Yazdi R. The presence of anti thyroid and anti ovarian auto- antibodies in familiar premature ovarian failure. International Journal of Fertility and Sterility. 2008;4(1)

171–174). Examples of the antigenic targets for antibody-mediated autoimmune damage in POF are: auto - antibodies to steroid producing cells, widely present in POF associated with

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11 Addison’s disease (Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity. (Falorni A, Laureti S, Candeloro P, Perrino S, Coronella C, Bizzarro A, Bellastella A, Santeusanio F, De Bellis A Fertil Steril.

2002 Aug; 78(2):270-9); enzymes involved in the steroid metabolic pathway like 3β-hydroxysteroid dehydrogenase (3β-HSD). Auto - antibodies to 3β-HSD were found in

2-21% patients with isolated POF (Identification of 3 beta-hydroxysteroid dehydrogenase as a novel target of steroid cell autoantibodies: association of auto - antibodies with endocrine

autoimmune disease. (Arif S, Vallian S, Farzaneh F, Zanone MM, James SL, Pietropaolo M, Hettiarachchi S, Vergani D, Conway GS, Peakman M J Clin Endocrinol Metab. 1996 Dec; 81(12):4439-45). In autoimmune ovarian failure, the elevated serum gonadotropin hormones result from the dysfunction of the ovarian follicles rather than follicular depletion (An update: spontaneous premature ovarian failure is not an early menopause. Nelson LM, Covington SN, Rebar RW Fertil Steril. 2005 May; 83(5):1327-32.

For long multiple endocrine auto - antibodies has been associated with POF. Virtually every autoimmune disorder has been reported in association with POF (Forges T, Monnier-Barbarino P, Faure GC, Bene M C. Autoimmunity and antigenic targets in ovarian pathology. Hum Reprod Update. 2004;10:163–175). The most common are endocrine autoimmunity like hypothyroidism, adrenal failure (Addison's disease) and type 1 diabetes mellitus (Rees M, Purdie D. Premature menopause In: Management of the Menopause: The Handbook (4th edn). London, UK: Royal Society of Medicine Press Ltd, 2006; 142–149). The typical endocrine autoantibody is a specific, circulating molecule that can be readily identified using indirect immunofluorescence.

3) Infection

POF has also been associated with infections such as mumps, tuberculosis, malaria, varicella, shigella, cytomegalovirus and herpes simplex (Morrison JC, Givens JR, Wiser WL, et al. Mumps oophoritis: a cause of premature menopause. Fertil Steril 1975;26:655–659)

4) Environment

There are many potential toxicants that has been proposed as predisposing factors in POF. The major adverse environmental influence is cigarette smoking. Ovarian diseases and

surgeries are associated with diminished ovarian reserve. Chemotherapy is an important risk factor as well, main ones are alkylating agents.

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12 5) Iatrogenic

Ovarian damage due to radiation and chemotherapy given for treatment of childhood malignancies can result in primary ovarian failure, even though pre - pubertal ovaries are more resistant to the harmful effects of radiation and chemotherapy than mature ovaries.

Iatrogenic POF has increased over time, because of the improved success in the treatment of cancer in children, adolescents, and reproductive-age women (Keshaavarz H, Hills SD,

Kieke BA, Marchbanks PA. Hysterectomy surveillance-United States, 1994-1999. Surveillance summaries. 2002;51(ss05):1–8). The radiosensitivity of the oocyte

is estimated to be 2 Gray (The radiosensitivity of the human oocyte. Wallace WH, Thomson AB, Kelsey TW Hum Reprod. 2003 Jan; 18(1):117-21). Radiation dose of ≥6 Gray produces

ovarian failure in virtually all individuals over 40 years of age. The effect of the therapy is dependent on dose and age, and radiation field. the functions of ovarian granulosa cells and oocytes may be affected by chemotherapeutic agents (Quantitative assessment of the

impact of chemotherapy on ovarian follicle reserve and stromal function. Oktem O, Oktay K

Cancer. 2007 Nov 15; 110(10):2222-9). Major predictive factors in the development of ovarian dysfunction after chemotherapy are age, drug type and its dosage. Additional

radiation to the treatment is also very important (Premature ovarian "failure" in the adolescent. Rebar RW Ann N Y Acad Sci. 2008; 1135():138-45). To evaluate the gonadotoxicity after chemotherapy the serum anti-mullerian hormone, as a biochemical marker of the ovarian reserve can be used (The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Anderson RA, Themmen AP, Al-Qahtani A, Groome NP, Cameron DA Hum Reprod. 2006 Oct; 21(10):2583-92).

6.3. Consequences arising from POF

a) Osteoporosis: Women with POF have significantly lower bone density (Anasti JN, Kalantaridou SN, Kimzey LM, et al. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998;91:12–15.; Uygur D, Sengül O, Bayar D, et al. Bone loss in young women with premature ovarian failure. Arch Gynecol Obstet 2005;273:17–19) and this is associated with a significantly higher overall fracture risk (van Der Voort DJ, van Der Weijer PH, Barentsen R. Early menopause: increased fracture risk at older age. Osteoporos Int 2003;14:525–530). There is evidence that

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13 the use of HRT for at least 3 years may help reduce subsequent fracture risk (van der Klift M, de Laet CE, McCloskey EV, et al. Risk factors for incident vertebral fractures in men and

women: the Rotterdam Study. J Bone Miner Res 2004;19: 1172–1180). Analysis of patients from the authors’ unit has shown that at the time of diagnosis 27.7% of

patients have osteopenia and 3.8% have osteoporosis (Panay N, Maclaran K, Nicopollous J, Horner E, Domoney C. Findings from the West London Menopause and PMS Centre POF Database (Abstract No. 337).

b) Cardiovascular diseases: A significantly increased risk of cardiovascular

disease has been demonstrated in women with POF, with an estimated 80% increased risk of mortality from ischemic heart disease in those with a menopause under the age of 40 years

compared to those with menopause at 49–55 years (Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total mortality and mortality from ischemic heart disease: the Adventist Health Study. J Clin Epidemiol 1999;52:303–307). This risk of ischaemic heart disease was more pronounced in those who had never used estrogens. POF has been

associated with several risk factors for the development of cardiovascular disease including impaired endothelial function (Kalantaridou SN, Naka

KK, Papanikolaou E, et al. Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy. J Clin Endocrinol Metab 2004;89:

3907–3913) adverse effects on the lipid profile (Knauff EA, Westerveld HE, Goverde AJ, et al. Lipid profile of women with premature ovarian failure. Menopause 2008;15:919–923)

reduced insulin sensitivity (Corrigan EC, Nelson LM, Bakalov VK, et al. Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women. Menopause 2006;13: 911–916) and the metabolic syndrome (Eshtiaghi R,

Esteghamati A, Nakhjavani M. Menopause is an independent predictor of metabolic syndrome in Iranian women. Maturitas 2010;65:262–266).

c) Cognitive impairment: It has been suggested that patients with POF may be at increased risk of dementia or reduced cognitive function. The Mayo Clinic Cohort Study

of Oophorectomy and Aging investigated the risk of cognitive impairment and Parkinsonism in women undergoing premenopausal oophorectomy. They demonstrated that women who underwent either unilateral or bilateral oophorectomy before the onset of the menopause had an increased risk of cognitive impairment or dementia (Rocca WA, Bower JH, Maraganore

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14 DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.

Neurology 2007;69:1074–1083) and Parkinsonism (Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008;70:200–209).

d) Infertility: Ovarian function can return intermittently in up to 50% of patients with POF and this can occasionally lead to ovulation and pregnancy. For most women wishing to conceive, in vitro fertilization (IVF) with donor oocytes confers the highest

chance of successful pregnancy. In patients with some remaining ovarian reserve at the time of diagnosis, ovulation induction with timed intercourse or intrauterine insemination may be an option. There is evidence to suggest that the success rate of ovulation induction with

exogenous gonadotrophins may be improved by pre-treatment with estrogen, by lowering

FSH levels (Tartagni M, Cicinelli E, De Pergola G, et al. Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with

premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril 2007;87:858– 861).

There have also been recent case reports about the use of 5-dehydroepiandrosterone (DHEA) leading to ovulation and spontaneous pregnancies in POF (Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Fertil Steril 2009;91:644–646). For women who require treatment for malignancy preservation of ovarian function may be achieved via ovarian transposition prior to radiotherapy. This is usually done laparoscopically and can greatly reduce radiation exposure of ovarian tissue. Cryopreservation techniques have received much interest in recent decades as they provide a potential means of preserving fertility in patients requiring chemotherapy (Nyboe Andersen A, Goossens V, Bhattacharya S, et al.; European IVF-monitoring (EIM) Consortium, for the European Society of Human Reproduction and Embryology (ESHRE). Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE:

ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2009;24:1267–1287).

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6.4. Pathophysiology of the POF

In 90% of cases the pathogenesis remains unknown. There are two mechanisms which are said to play the main roles in POF pathophysiology.

One of them is ovarian follicle depletion. In female humans, germ cells stop dividing and enter meiosis at around 20 weeks of fetal life, reaching a maximum of 7 million. Thereafter, this resting follicle pool is depleted throughout the life in a logarithmic fashion.

At menarche, the primordial follicle pool is depleted to around 500,000. The pool is exhausted, coinciding with menopause (Wise PM, Krajnak KM, Kashon ML. Menopause:

the aging of multiple pacemakers. Science 1996;273:67–70). Age at menopause varies, the mean age is 51 years. Individual differences in the rate at which the primordial follicles leave the resting pool by initiation of growth or by direct atresia should be considered. Epidemiologic studies have demonstrated a familial component in ovarian senescence. The menopausal age of a given women is correlated with timing of menopause in her mother and sister, strongly suggesting a genetic component in factors regulating depletion of the follicle pool. Moreover, various regions located on the X chromosome are clearly related to early

menopause, as shown by the occurrence of mosaic Turner syndrome, deletions of the X chromosome, and the fragile X syndrome in women presenting with premature ovarian

failure. Parity and environmental factors, such as nutrition, race, and socioeconomic status, also influence age at menopause. Increasing evidence suggests that smoking is yet another factor. Depletion of ovarian follicles with POI leads to a decline in estradiol, anti-Müllerian hormone and inhibin B levels, and a rise in pituitary gonadotrophins (Vincent A, Farrell E. Premature menopause.

Current topics in menopause. Emirate of Sharjah, United Arab Emirates: Bentham Science Publishers, 2012; p. 414–41).

The other one affects female reproductive system is an ovulatory dysfunction, complex interaction of many hormones. The most important are FSH, LH, estrogen and progesterone. Hormone regulatory function is coordinated by hypothalamus. This is a small gland located at the base of the brain by which levels of various hormones is monitored. Hypothalamus sends ―instructions‖ to the pituitary gland via hormone mediators where it is needed to keep the hormonal balance in the organism. In the healthy woman’s body FSH is secreted by the pituitary gland and causes the recruitment and development of ovarian follicles. During the first part of the menstrual cycle, levels of FSH increase to stimulate

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16 follicular development. Hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the pituitary to produce FSH. As healthy follicles develop, they secrete increasing amounts of estrogen, which is monitored by the hypothalamus.

Once the hormone levels indicate that the follicles are mature, the hypothalamus signals the pituitary to release a surge of LH, which induces the final steps of egg maturation and triggers ovulation. Disruption of any of these processes can lead to irregular (oligoovulation) or no (anovulation) ovulation. Women are born with a lifetime supply of eggs and as they age the ―quality‖ and ―quantity‖ of their eggs declines, ultimately ending in menopause. Furthermore, some women experience premature ovarian failure seeing a decline in the number of available eggs while still in their twenties or thirties.

Ovarian failure can be called as hypergonadotrophic hypogonadism which is defined by lowered androgen levels. It is possible that also testosterone concentrations might be above

the lower limit of the normal range. We observe significantly elevated levels of LH and FSH in ovarian failure. Women with hypergonadotrophic hypogonadism are said to have premature ovarian failure, when are under age 40. POF can be complete or partial. In this condition girls may start but not progress through puberty, or they may present with complete sexual infantilism.

6.5. Clinical presentation of the POF

The symptoms may vary from patient to patient. POF may occur abruptly or it may develop over several years. The most severe form of POF is hypergonadotropic form. In such

situation we observe absence of pubertal development and primary amenorrhea. The clinical features are characterized by absence of menarche and pubertal delay. In results a girl with hypergonadotropic POF doesn’t go into sexual maturation and has reduced growth

velocity. In the female gender pubertal delay is defined as the absence of mammary, pubic

hair and menarche at 13 years. In such patients it is possible to see moderate hirsutism due to actions of androgenic hormones.

As it was said before, one of the main reason for POF to occur is ovarian dysgenesis, that’s why primary amenorrhea can be seen. During ultrasound examination in such case

streak ovaries and uterus hypoplasia also smaller follicles can be found. Almost normal pubertal development may be seen.

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17 In the majority of female patients the most common is post pubertal onset of the POF (1). This is characterized by secondary amenorrhea associated with premature follicular depletion or arrested folliculogenisis. It is represented by physiological menopause.

Main features are heart palpitations, heat intolerance, flushes, night sweats, irritability, anxiety, depression, sleep disturbance, hair coarseness, vaginal dryness, fatigue. The most common presenting symptom is menstrual disturbance. POI can have a significant negative impact on physical and emotional wellbeing, including menopausal symptoms, infertility and increased risk of long-term consequences (Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature menopause or early menopause: Long-term health consequences. Maturitas 2010;65(2):161–66). Menopausal symptoms may be more severe in women with premature menopause, compared with natural menopause, whereas women with primary amenorrhoea are unlikely to experience menopausal symptoms (Webber L, Davies M, Anderson R, et al. ESHRE guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016;31(5):926–37).

Infertility is a key feature of POF due to loss of ovarian reserve. In women with spontaneous Fitness for pregnancy requires assessment in the preconception period as some women with POF may have high obstetric risk, such as women with Turner syndrome (Bondy CA. Care of girls and women with Turner syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92(1):10–25).

Women with POF may present with adverse psychosocial symptoms, and have been found to have higher levels of depression and anxiety, a more negative body image, decreased sexual function and reduced confidence (Deeks AA, Gibson-Helm M, Teede H, Vincent A. Premature menopause: A comprehensive understanding of psychosocial aspects. Climacteric 2011;14(5): 565–72). They may express grief at the loss of femininity and fertility, fear of

long-term health consequences related to POI, and concerns regarding the effects on the relationship with their partner. POI may be diagnosed as a consequence of a comorbid

condition, and the clinical presentation may be related to the underlying cause, such as thyroid or adrenal autoimmune conditions or cancer-related medical therapies.

6.6. Diagnosis of the POF

There is no consensus on criteria to identify primary ovarian insufficiency in adolescents, and delay in diagnosis is very common. POI should be considered in any

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18 woman before age of 40 years presenting with a history of menstrual disturbance, especially oligomenorrhoe or amenorrhoea, regardless of whether they have symptoms of oestrogen deficiency or not. Further, girls who have not undergone menarche by 15 years of age should be investigated for primary amenorrhoea (Adams Hillard PJ. Menstruation in adolescents: What do we know? And what do we do with the information? J Pediatr Adolesc Gynecol 2014;27(6):309–19). Typically in presentation with possible POF diagnosis will be a woman

under 40 years old who presents with menstrual irregularity or amenorrhea for more than 4 months.

Diagnosis of POI can be difficult because of the variable and fluctuating

presentation, reflecting fluctuating ovarian activity. Women with POF may present in different of ways. Most commonly it is with secondary amenorrhea or menstrual

irregularity and this may or may not be associated with the common symptoms of estrogen deficiency. A small percentage will present with primary amenorrhoea, in which case an underlying chromosomal cause is more likely (Panay N, Maclaran K, Nicopollous J, Horner E, Domoney C. Findings from the West London Menopause and PMS Centre POF Database (Abstract No. 337). Proceedings of the 32nd British International Congress of Obstetrics and Gynaecology, Belfast, Northern Ireland, UK, 20–23 June 2010). Therefore, in young females

it is important to evaluate amenorrhea or a change from regular to irregular menses for 3 or more consecutive months in the absence of hormonal preparations such as oral

contraceptives for all potential causes (Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med 2009;360:606–14; Nelson LM. Spontaneous premature ovarian failure: young women, special needs. Menopause Manag 2001;10(4):1–6). Family medical history should be taken because females with a family history of early menopause are at risk of primary ovarian insufficiency (Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. ACOG Committee Opinion No. 349. Obstet Gynecol 2006;108:1323–8). A detailed menstrual history about age of menarche, frequency and pattern of menses and date

of last menstruation is useful to determine any menstrual alteration early in the course of events. Present of menopausal symptoms such as mood lability, insomnia, irritability, hot

flushes and night sweats. Urogynecological and sexual changes such as amenorrhea, valve-vaginal atrophy, low libido, dyspareunia shild be considered. Obstetric and gynecological problems such as uterine or ovarian surgery, psychological and sexual function and very important presents of autoimmune diseases, especially adrenal and thyroid abnormalities. Past

medical conditions including previous cancer and related treatment (radiotherapy or chemotherapy), viral illness such as mumps, eating disorders, osteoporosis should be

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19 included in the medical interview. Of importance is patient’s life style and related with risk factors for POF.

History of smoking, alcohol consumption, diet, physical activity should be noted since it is not uncommon for these conditions to be seen in patients with POI. Tobacco exposure

(active as well as passive) has been associated with early menopause and is a recognized detriment to ovarian biology (Schoenaker DA, Jackson CA, Rowlands JV, et al.: Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. Int J Epidemiol. 2014; 43(5): 1542–62.;

European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, et al.: ESHRE Guideline: management of women with

premature ovarian insufficiency. Hum Reprod. 2016; 31(5): 926–37). Information on maternal

age at menopause and family history of POI in first- or second-degree relatives may be pertinent, as can a history of mental retardation, recurrent pregnancy loss, and history of any known autoimmune or genetic disorders in family members. A thorough review of systems should enquire about symptoms of fatigue and weight fluctuations and focus on,

among other things, any involvement of the musculoskeletal and integumentary systems. Medications play an important role in diagmosis of the POF. It’s useful to ask about combined oral contraceptive pills, estrogen hormone therapy, tamoxifen and aromatase inhibitors.

Physical examination should focus on signs of any underlying disorder. Skin depigmentation or hyperpigmentation may reflect underlying autoimmune disorder. Evidences of estrogen deficiency can be presented by lack of or delayed secondary sex

characteristics or features of genital atrophy. Doctor should also asses breast development

in patient. During examination we should also look for any phenotypic hallmarks of a chromosomal disorder like a short height, cubitus valgus, and dorsal cervical fat pad

which are typical for Turner syndrome ( Abir R, Fisch B, Nahum R, et al.: Turner's syndrome and fertility: current status and possible putative prospects. Hum Reprod Update. 2001; 7(6): 603–10). Weight and height should be measure and patient’s BMI should be calculated, also cardiovascular examination sometimes can be useful.

Diagnosis of POI requires FSH levels in the menopausal range on two occasions at least four to six weeks apart in a woman aged <40 years after more than four months of amenorrhoea or menstrual irregularity, and after secondary causes of amenorrhoea have

been excluded (Figure 2). According to International Menopause Society (IMS) guidelines, 15 an FSH level >40 IU is used to define the menopausal range, while recent guidelines from

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20

the European Society of Human Reproduction and Embryology (ESHRE) recommended an FSH level >25 IU.

It is important that women are not taking hormonal contraceptives or HRT, to ensure accurate interpretation of the hormone levels. These agents must be withdrawn for at least six weeks prior to hormone measurements. The routine use of anti-Müllerian hormone levels in the diagnosis of POI is not currently recommended as its accuracy is not validated in this setting.

Initial laboratory evaluation includes measurements of basal FSH and basal estradiol levels and tests to rule out pregnancy, such as β-HCG (high chorionic gonadotropin) measurement. TSH (thyroid stimulating hormone) level should be on the list of the tests in initial evaluation. Pelvic ultrasound can also give the doctor an important clue about the diagnosis. Gonadotropin and estradiol values may be altered by concomitant use of hormonal preparations and thus should only be obtained in patients who are not taking hormonal medications, including oral contaceptives. If gonadotropins are elevated into the menopausal range, more than 25-40 IU on two occasions more than 4-6 weeks apart. If the result indicates

that FSH is elevated, a diagnosis of primary ovarian insufficiency can be established.

If FSH level will be in a normal range we should look for other causes of oligo or amenorrhea. Possible cause can be pregnancy, polycystic ovarian syndrome,

hyperprolactinemia. Low BMI may indicate eating disorders. Estradiol levels of less than 50 pg/mL indicate hypoestrogenism. It is commonly accepted that estimation of gonadotrophin levels should be performed after 3–4 months of amenorrhea or menstrual irregularity. If these

are within the menopausal range they should be repeated after 4 weeks along with estradiol to confirm hypogonadism. Assessment of thyroid function and prolactin is also recommended

to exclude alternative pathology. Pelvic ultrasonography should be considered, as the antral follicle count is severely reduced in POF.

A further diagnostic tool is anti-Müllerian hormone (AMH). AMH, produced by developing antral follicles, is currently thought to be the most reliable measure of reduced ovarian reserve. AMH is not cycle-dependant and can therefore be estimated at any time in

the menstrual cycle. Markedly low to undetectable serum levels of AMH in the setting of elevated FSH and suppressed estradiol levels reaffirm the impression of POF (Visser JA,

Schipper I, Laven JS, et al.: Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat Rev Endocrinol. 2012; 8(6): 331–41). A pelvic ultrasound, preferably using a transvaginal approach, can further confirm concerns for ovarian compromise. In appropriate clinical settings, evidence of a thin endometrial echo (<4 mm),

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21

small ovarian volumes, and low antral follicle counts (<5) are all consistent with a picture of POF; however, radiological imaging is not essential to establish the diagnosis.

Once the diagnosis has been confirmed investigations to look for an underlying cause should be done. Exposure to chemotherapy with alkalyting agents can indicate iatrogenic cause of POF. Spontaneous POF can occur with abdominal-pelvic radiotherapy. Screening for the FMR1 gene premutation is especially important in younger patients, or those with a family history of POF or learning difficulties, to exclude an underlying genetic cause. Karyotype testing is indicated when Turner syndrome or other chromosomal abnormalities is suspected. Baseline autoimmune screening, for antiadrenal, antiovarian antibodies and thyroid auto-

antibodies is recommended for the patients. This may identify an underlying cause or highlight those patients at increase of autoimmune disorders. Coelliac serology can also be a useful test in investigating the cause.

The differential diagnosis is based on exclusion of other causes primary and secondary amenorrhea which are main signs in POF. Pregnancy first important cause to rule out, presents with high level of β- HCG. Iatrogenic causes such as surgery, anti - neoplastic treatments, radiations, anti - dopaminergic drugs. Hypothalamic-Pituitary disease such as pituitary tumors, hyperprolactinemia, Kallmann syndrome: high prolactin and low or normal gonadotropin levels, alterations at imaging of brain or sella region. Hypothalamic amenorrhea induced by stress, intensive exercises, anorexia, weight loss, fasting with low or normal gonadotropin levels. Polycystic ovarian syndrome characteristics with alterations at ovarian ultrasound, normal level of gonadotropin and high androgen levels. Enzyme defects during steroidogenesis process such as 21-hydroxylase deficiency with alterations at physical and adrenal ultrasound, normal gonadotropin, high androgen and ACTH (adrenocorticotropic hormone) levels. Endocrine disorder like hyper/hypothyroidism, Addison disease, Cushing syndrome. In primary amenorrhea in differential diagnosis we should keep in mind syndromes like Rokitanski syndrome or Asherman syndrome in which we can observe vaginal/uterus anatomical abnormalities. Disorders of sexual differentiation should also be considered (Beck-Peccoz Pablo, Persani Luca, Premature Ovarian Failure, Orphanet Journal of rare diseases april 2006).

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22

6.7. Treatment of the POF

Women with POF should ideally be managed within specialist multidisciplinary teams to address their complex physical and psychological needs. Team is consisted of the gynecologist, menopause nurse specialist, psychologist, psychosexual counselor and dietician. It’s very important to inform a patient about diagnosis in supportive and sensitive manner. General lifestyle and dietary measures should be recommended to all patients, to reduce the risks of development of cardiovascular disease and osteoporosis. In case of suspected reduced bone density supplementation of calcium and vitamin D should be considered. Recommended dose for daily intake of those supplements is 100 mg and 800 IU of calcium and vitamin D respectively. Life style modification if it’s necessary should be advised to the patient. Regular weight bearing exercise, minimizing smoking and reduction of alcohol and caffeine intake will have beneficial effects. Healthy diet is one of the important factor to reduce long term adverse consequences of POF. There are few solutions how to manage POF:

a) Hormonal replacement therapy (HRT)

Estrogen replacement should be offered to women with POF to help to reduce the symptoms of estrogen deficiency and to minimise the risks of development of osteoporosis and cardiovascular disease (British Menopause Society (BMS). Premature Menopause. British Menopause Society Council Consensus Statement. 2007. http://www.thebms.org.uk/statementpreview.php?id=3 [accessed 14 September 2010]).

Various factors require consideration in the selection of HRT preparations, and HRT should be individualised to improve adherence, taking into account women’s wishes. For example,

oestrogen-only therapy in women is recommended for women who have had a hysterectomy, cyclical progestin combined with estrogen for women who prefer monthly withdrawal bleeds (or continuous combined therapy in those who do not) and transdermal estrogen for women

at increased risk of venous thromboembolism, migraines or liver disease. HRT may be preferable to COCP for optimization of the bone health, but must be weighed against the

need for contraception. In adolescents, hormone replacement may be required to help induce

secondary sexual characteristics. Patients with POF will typically require higher doses of estrogen than older postmenopausal women. Administration of 100 µg 17β-estradiol by

transdermal patch achieves serum estradiol levels equivalent to premenopausal mid-follicular estradiol levels (300– 400 pg/ml). Transdermal route

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23 of hormonal replacement is very beneficial. Helps to avoid first-pass hepatic metabolism and subsequent effects on clotting factors and triglycerides. In non-hysterectomised women, estrogen therapy must be given in combination with a progesterone to provide endometrial protection. Women with POF have been shown to have lower androgen levels (van der Stege JG, Groen H, van Zadelhoff SJ, et al.

Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure. Menopause 2008;15:23–31). Consideration therefore should

also be given to androgen replacement, especially in those suffering from symptoms of testosterone deficiency, such as reduced libido or lethargy. Serum testosterone levels

should be kept within the physiological range to minimize the risks of side effects such as unwanted hair growth and acne. For some women, the COCP will be a more acceptable method of hormone replacement. COCPs deliver synthetic hormones in supra-physiological doses, but women often see the COCP as a simpler and more peer-friendly regimen than HRT. There are a few contraindications to HRT. Patients with hormone-sensitive malignancies such as estrogen receptor-positive breast cancer or endometrial cancer or those at high thromboembolic risk or with endometriosis may choose to use non-hormonal treatment options. Doctors should weight up risks and benefits and informed decision should be made carefully. At present there is not much evidence regarding the efficacy of non

hormonal therapies such as selective serotonin re-uptake inhibitors (SSRIs), venlafaxine or gabapentin. They can provide some symptomatic relief but will not to act to reduce the

long-term effects of estrogen deficiency.

Another important point in choosing proper treatment solution is woman wish for pregnancy. Unpredictable return of ovarian function may occur and spontaneous

pregnancies have been observed in 5–10% of women with POF (van Kasteren YM,

Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999;5:483–492).

As HRT is not contraceptive method, counselling regarding contraceptive options is important for women not desiring pregnancy. COCP can provide both hormone

replacement and contraception. Patient should be advised to take it continuously or long cycle, without the inactive pills. The reason for this pattern of treatment is to avoid intermittent periods of symptomatic estrogen deprivation (Webber L, Davies M, Anderson R, et al. ESHRE guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016;31(5):926–37). Forms of contraception like progesterone only pills, depot

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24

For those patients using of the transdermal estrogen with the levonorgestrel IUD can be an option. They will provide contraception, symptom management and prevention of long

term sequelae. Women should be reviewed frequently while the dose of HRT is titrated.

Once a maintenance dose is established, consultations should occur at least annually to monitor for symptom control and to complete an annual complication screen.

b) Sexual dysfunction and psychological support

A sexual health history is very important in POF. Women are often reluctant to disclose sexual dysfunction. Key treatment issues to consider include optimization of HRT,

treatment of urogenital symptoms such as vaginal oestrogen or lubricant to treat dyspareunia. Important step is also review of medications that can have an impact on sexual function; main ones are antidepressants and aromatase inhibitors (Vincent A, Farrell E. Premature menopause. Current topics in menopause. Emirate of Sharjah, United Arab Emirates:

Bentham Science Publishers, 2012; p. 414–41). One of the reasons that may contribute to sexual dysfunction in POF is low female androgen level (Webber L, Davies M, Anderson

R, et al. ESHRE guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016;31(5):926–37; Vincent A, Farrell E. Premature menopause. Current topics in menopause. Emirate of Sharjah, United Arab Emirates: Bentham Science Publishers, 2012; p. 414–41).

Women with POF have been shown to have increased anxiety, depression and somatisation, with reduced self-esteem and overall life satisfaction (van der Stege JG, Groen H, van Zadelhoff SJ, et al. Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure. Menopause 2008;15:23–31; Schmidt PJ, Cardoso GM, Ross JL, et al. Shyness, social anxiety, and impaired self-esteem in Turner syndrome and premature ovarian failure. JAMA 2006;295:1374–1376; Liao KL, Wood N, Conway GS. Premature menopause and psychological well-being. J Psychosom Obstet Gynaecol 2000;21:167–174). Psychological support is a vital aspect of the management of the patients with POF.

c) Lifestyle modification

Menopausal symptoms and reduction of CVD or osteoporosis risk can be addressed by dietary and lifestyle modification (Nelson LM. Clinical practice. Primary ovarian

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25 insufficiency. N Engl J Med 2009;360(6):606–14). These include smoking cessation, healthy weight maintenance, adhering to recommended alcohol intake, regular weight-bearing exercises, adequate calcium intake and sufficient vitamin D levels.

d) Genetic counseling

Counseling it is important part of diagnosis and future treatment plan for the patient. It also has a psychological aspect in POF; to know and understand a problem. It’s highly

recommended when genetic form of POF is suspected or identified. It is of particular importance in POF related with X-linked mental retardation (8). All women with diagnosed POF before age of 30 should perform blood tests for chromosomal assessment. With older females this option should be discussed. Carriers of the genetic defect may be an indication for early pregnancy or oocyte collection and preservation.

e) Management of long term health consequences

 Osteoporosis: screening with DXA scan is highly recommended and it is advise to repeat the scan every two years. If it’s abnormal secondary causes of the

osteoporosis need to be treated. To maintain bone health and to prevent osteoporosis early start of HRT is recommended. Monitoring vitamin D level and if it’s lower than required

amount replacement may be needed. Lifestyle modification it’s an important factor in prevention. If bone density is declining despite HRT appointment with specialist doctor is highly advised. Then initiation of specific treatment and future steps can be planned. It’s important in young adult population and patients who desire pregnancy.

6.8. Pregnancy among women with POF

Normal function of the ovaries, which is responsible for the hormonal and reproductive processes, is one of the most important determinants of fertility. For the POI

patient, fertility and pregnancy achievement is one of the most dramatic problems. It influences women’s psychological status and their functioning in society. The chance for

spontaneous conception is very limited. For contemporary medicine, infertility treatment in POI patients is a challenge. Signs of intermittent ovarian function in karyotypically normal

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26 women have been described (Barbarino-Monnier P. From pathological diagnosis to ovulation induction. The case of ovarian insufficiency. [Article in French]. Gynecol. Obstet. Fertil. 29,

39–48 (2001)). Collected data shows that ovarian function can return intermittently in up to 50% of women with POF.

Because of this fact sometimes it can lead to ovulation and pregnancy. For most women wishing to conceive, in vitro fertilization (IVF) with donor oocytes confers the highest chance of successful pregnancy, with success rates of 40–50% per cycle. However, nowadays we can observe important progress in the development of fertility preservation methods. In the POF field it refers to cryopreservation of oocytes, embryos, and ovarian tissue. Additionally, new methods known as in vitro activation of dormant follicles and possible use of stem cells should be mentioned as a new possibilities for the couples.

The most successful and ultimate treatment of these infertile couples is egg donation (ED) (Shelling AN. Premature ovarian failure. Reproduction 140(5), 633–641 (2010)) which is an assisted reproductive procedure that widely practiced in most countries. Oocyte donation in POF patients presents quite high efficacy. According to Ameratunga et al. (Ameratunga D, Weston G, Osianlis T, et al. In vitro fertilisation (IVF) with donor eggs in post-menopausal women: are there differences in pregnancy outcomes in women with premature ovarian failure (POF) compared with women with physiological age-related menopause? J Assist Reprod Genet. 2009;26:511–514), the pregnancy rate after an oocyte donation cycle is around 40%, and cumulative pregnancy rates after four cycles reach 70-80%. Turner syndrome patients are also candidates for in vitro fertilisation with oocyte donation. However, it is well known that in these patients a high rate of cardiovascular anomalies is observed. Therefore, according to the American Society of Reproductive Medicine (ASRM), women with Turner syndrome before attempting to become pregnant should undergo medical and cardiovascular control (Practice Committee of American Society For Reproductive Medicine Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril. 2012;97:282); this can decrease the high rate of cardiovascular mortality during pregnancy. The procedure of oocyte donation can be used also in cancer survivors. Oocyte donation pregnancies are associated with a higher rate of placental disorders of pregnancy, such as gestational hypertension and pre-eclampsia (Savasi VM, Mandia L, Laoreti A, Cetin I. Maternal and fetal outcomes in oocyte donation pregnancies. Hum Reprod Update. 2016;22:620–633).

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27 In patients with some remaining ovarian reserve at the time of diagnosis, ovulation

induction with timed intercourse or intrauterine insemination may be an option. The majority of published reports on induction of ovulation use a technique to restore sensitivity of those

follicles that are resistant to FSH. This solution is effective only in minority of treated women. When the most possible cause of POF is autoimmunity then it’s reasonable to try the combination of a GnRH-a, ovulation induction with relatively high doses of gonadotropins and small doses of glucocorticosteroids (Badawy A, Goda H, Ragab A. Induction of ovulation in idiopathic premature ovarian failure: a randomized double-blind trial. Reprod. Biomed. Online 15, 215–219 (2007)).

There is evidence to suggest that the success rate of ovulation induction with exogenous gonadotrophins may be improved by pre-treatment with estrogen, by lowering FSH levels

(Tartagni M, Cicinelli E, De Pergola G, et al. Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril 2007;87:858–861). There have also been

recent case reports about the use of 5-dehydroepiandrosterone (DHEA) leading to ovulation and spontaneous pregnancies in POF (Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Fertil Steril 2009;91:644–646). Pregnancy rates generated in these patients depend not only on the ovarian reserve and the age, but also on the type of infertility, the cycle number and the uterus (Merviel P, Lourdel E, Boulard V et al. Premature ovarian failure: which protocols? Gynecol. Obstet. Fertil. 36, 872–881 (2008)).

In women with iatrogenic causes such as previous oncological treatment or planned chemotherapy there are two solutions. Cryopreservation of embryos or fertilized oocytes after IVF and before chemotherapy [(Sklar CA, Mertens AC, Mitby P et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J. Natl Cancer Inst. 98, 890–896 (2006)); van der Kaaij MA, van Echten-Arends J, Simons AH, Kluin-Nelemans HC. Fertility preservation after chemotherapy for Hodgkin lymphoma. Hematol. Oncol. 28(4), 168–179 (2010))]. IVF might be irrelevant or equivocal in patients who need urgent chemotherapy, or in diseases that may be aggravated by the pharmacological levels of estrogens, such as systemic lupus erythematosus or breast cancer (Blumenfeld Z. Premature ovarian failure: etiology and possible prevention. Expert Rev. Endocrinol. Metab. 4, 173–181 (2009). Advancement in fertility preservation gives an optimistic perspective for many POF patients. Fertility preservation can concern cryopreservation of oocytes, embryos, and ovarian tissue. There are still technical problems with the cryopreservation of oocytes

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28

because oocytes contain more water and are more susceptible to cryoinjury. Cryopreservation of ovarian tissue can also be a method for women who have hormone-sensitive malignancies,

and for women anticipating haematopoietic stem cell transplantation for the treatment of benign haematological diseases (sickle cell anaemia, thalassemia major, aplastic anaemia)

(Albani E, Bracone G, Biccari SD, et al. Human ovarian tissue cryopreservation as fertility reserve. In: Mohan R, editor. Topics in cancer survivorship. London: IntechOpen Limited; 2012. p. 215).

Ovarian tissue cryopreservation and transplantation is still regarded as experimental.

The biggest worldwide report on ovarian transplantation tissue was published in 2016. It includes 95 orthotopic transplantations of ovarian tissue in 74 women after cytotoxic

treatment in a fertility preservation network (16 centres in Europe).

Twenty-one pregnancies and 17 deliveries were reported (Van der Ven H, Liebenthron J, Beckmann M, et al. Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates. Hum Reprod. 2016;31:2031–2041).

Stem cells have self-renewal and regeneration potential; hence they can be very effective in the treatment of ovarian failure and consequently infertility (Sheikhansari G, Aghebati-Maleki L, Nouri M, et al. Current approaches for the treatment of premature ovarian failure with stem cell therapy. Biomed Pharmacother. 2018;102:254–262). There are several kinds of stem cells, such as: mesenchymal stem cells (MSCs), stem cells from extraembryonic tissues, induced pluripotent stem cells (iPSCs), and ovarian stem cells that are used in POF stem cell therapy, as observed in previous studies. Stimpfel et al. (Stimpfel M, Skutella T, Cvjeticanin B, et al. Isolation, characterization and differentiation of cells expressing

pluripotent/multipotent markers from adult human ovaries. Cell Tissue Res. 2013;354: 593–607). successfully characterised and differentiated in vitro stem cells from the adult

human ovarian cortex. The question is related to the application of these cells into the therapy

of infertility in POI patients. It may open a completely new chapter in the treatment of premature ovarian insufficiency.

6.9. POF among women after oncological treatment and their

pregnancy

Oncological treatment is one of the main cause of POF among young women. Most often they need to face with breast cancer, leukemia, lymphoma, melanoma and cervical cancer. Therapy

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