Women’s Health

Open journal

ISSN 2380-3940

Premature Ovarian Insufficiency: Aetiology and Long-Term Consequences

Naina Kumar, and Isha Manesh

Naina Kumar, MD

Associate Professor Department of Obstetrics and Gynecology Maharishi Markandeshwar Institute of Medical Sciences and Research Mullana-133207, Ambala, Haryana, India; Tel. +91-9552515600; E-mail: drnainakumar@gmail.com

INTRODUCTION

Premature ovarian insufficiency (POI) also known as Premature ovarian failure or Hypergonadotropic ovarian failure or Menopausa precoce1 is defined as a primary ovarian defect, characterized by an absent menarche (primary amenorrhea) or premature loss of ovarian follicles before 40 years of age (secondary amenorrhea).2,3 Characteristic features include cessation of ovulation or amenorrhoea for 4 months or more, hypoestrogenism (estradiol levels <50 pg/ ml)4 and high serum gonadotropin levels,5,6 especially two serum follicle-stimulating hormone (FSH) levels (>4 weeks apart) in menopausal range7,8 (>40 IU/l).4

POI was previously known as premature menopause, but this term is a misnomer, as all women with POI do not always stop menstruating, neither do their ovaries shut down completely.8 In most women aged >40 years, there is a physiological decline in ovarian function with aging which is called as perimenopause/menopausal transition.9 Ovarian ageing resulting in ovarian failure and menopause is a continuous process5,10 and menopause is usually attained at 51 years (range 40-60 years).11,12,13 The World Health Organization (WHO) defines menopause as permanent cessation of menstruation due to ovarian follicular activity loss.13

POI differs from menopause as, in POI unpredictable and varying degrees of ovarian functions are still present in 50% of women, and about 5-10% can even conceive and deliver child after diagnosis and treatment.7,8,14 It is a hypergonadotropic and hypogonadism state resulting from depletion/dysfunction of ovarian follicles due to either low initial numbers or accelerated loss.15 Premature loss of ovarian function leads to significant long-term psychosocial sequelae and major health complications.16 It also results in age-specific increase in mortality rate.17,18

Based on the age of onset, POI can present itself as primary amenorrhea, without onset of menarche, or secondary amenorrhea after puberty.3 It is a continuum of disorders with four clinical states which are not permanent. Patients usually budge from one state to another in an unknown manner.19 These states are as follows:

1. Occult POI presents as unexplained infertility with normal baseline serum FSH levels.

2. Biochemical POI presents as unexplained infertility with elevated basal serum FSH levels.

3. Overt POI previously known as premature ovarian failure is characterized by elevated serum FSH levels with associated menstrual disorders like oligomenorrhea, polymenorrhea, and metrorrhagia.

4. POI is an extreme state of total primordial follicle depletion; an irreversible state characterized by anovulation, amenorrhea, infertility, and elevated gonadotropin levels.

Incidence

POI is relatively common, with an estimated occurrence of 1 in 100 by 40 years; 1 in 1000 by 30 years11,12 and 1 in 10,000 by 20 years of age.1,20,21 It affects around 1-3% of women in the reproductive age below 40 years and around 0.1% in women below 30 years of age.2,10,18,22,23 Women with POI, around 10-28% experience primary amenorrhea and 4-18% secondary amenorrhea.10,18 Incidence of spontaneous onset POI has increased due to increasing success rates of cancer treatment in girls and young women.20,24,25 On the other hand, familial POI accounts for 15- 30% of all cases.1,12,26

Pathogenesis

Process of human folliculogenesis being highly complex and organised, is characterised by progressive maturation of small primordial follicles to larger ovulatory follicles. This whole process occurs continuously, and can stretch over a period of a year.27 Reproductive life span of human females start with a fixed number of primordial follicles,28 of which only 400-500 develop and ovulate before physiological menopause (Figure 1).29

Figure 1: (A) Normal Physiology of Foloocular Development. (B) Mechanism of Origin of Premature Ovarian Insufficiency.29

 

WHOJ-3-121Fig1

 

On the other hand, exact mechanism for development of POI is not known. It can be due to: a) Preliminary decrease in primordial follicle pool; b) Accelerated atresia of follicles; c) Defective maturation/recruitment of primordial follicles (Figure 1).29 Furthermore, accelerated follicular atresia can be because of changed apoptosis rate, defective follicle maturation blocking and abnormalities in primordial follicle activation that causes decreased number of available functional follicles/accelerated atresia.30,31

Hence, factors that initiate such mechanisms are highly heterogeneous and can be a result of, genetic mutations, chromosomal, infectious, autoimmune, metabolic and iatrogenic factors.18,29

AETIOLOGICAL FACTORS

Genetic Factors

Genetic factors are most commonly responsible for POI accounting for 7% of all cases.3,5,32 X chromosome is most commonly affected, but autosomal involvement is also common.18,33 Aneuploidies and rearrangements are most commonly reported with POI34 (Figure 2).29

 

Figure 2: Genes involved in Pathogenesis of Premature Ovarian Insufficiency.29

 

WHOJ-3-121Fig2

X CHROMOSOME

Monosomy (45 X)

Terminal deletions of long arm of X chromosome result in primary amenorrhea and absence of breast development in all cases.12,35 Total or near total absence of single X chromosome,18 known as Turner’s syndrome affects around 1 in 2500 live female births and is usually associated with ovarian dysgenesis leading to primary amenorrhea. However, 3-5% of such females with Turner mosaic karyotype can menstruate and even develop secondary sexual characteristics. Turner syndrome is associated with 4-5% POI cases.12,36,37

Trisomy

Trisomy affects 1 in 1000 women.12,18 Trisomy X females usually have normal ovarian function, but in some, it may manifest as early menopause, secondary amenorrhea, oligomenorrhea.10,38 Around 10% of females have mosaicism with 46, XX/47, XXX or 45, X/47, XXX karyotypes. Manifestations depend on time at which causing events occurred.10 Ovarian failure in females with 47, XXX (mosaic/non-mosiac) can be due to meiotic inadequacy of three X chromosomes, which is still unproven.10,34 However, cytogenetic studies in women with POI have shown that trisomy X (mosaic/non-mosaic patterns) have very low incidence of POI.10,39,40

Fragile X Syndrome

Fragile X syndrome is an X-linked dominant genetic condition characterised by expansion of trinucleotide repeat41 with prevalence of 1/6000 in females and 1/4000 in males.42,43 It is a common cause of hereditary mental retardation and developmental delay.43,44 Fragile X mental retardation 1 (FMR1) gene is located on X chromosome at Xq27.3. There is expansion of CGG trinucleotide repeats in 5′ untranslated region of first exon of FMR1 gene. Affected females show >200 CGG repeats, as compared to normal (5-54 CGG repeats). This expansion of >200 repeats causes methylation-coupled silencing of FMR1 gene resulting in loss of FMR-protein which is important for brain development in prenatal and postnatal period.41,43,45

Recently, it was reported that higher number of CGG repeats (>30-40) can be used to detect premature ovarian aging and POI in infertile women.43,46 An estimated 16-26% of female with FMR1 premutation carriers develop POI,43,47,48 whereas only 2% of normal women develop isolated POI.49 They are also known to develop tremor-ataxia syndrome,50 mild neuro-cognitive dysfunction.51 It was also reported that paternally inherited Fragile X premutations were more likely to be associated with POI as compared to maternally inherited permutations.52

Bone Morphogenetic Protein 15 Gene (BMP15)

Bone morphogenetic proteins (BMPs) are proteins belonging to transforming growth factor-β (TGF-β) superfamily, which play an important role in oocyte-specific growth/differentiation factors that help in follicle maturation and granulosa cell growth.18,29,53,54 BMP15 gene is located on the short arm of Chromosome X (Xp11.2) within ‘POI critical region’.18,29,55 BMP15 mutations are associated with 1.5-12% of POI cases.1,56,57,58,59,60 This defect is an unusual example of X-linked disease in which affected females inherit mutation from their unaffected father.1,56

Autosomal Genes

Genetic studies have shown various isolated gene defects associated with POI, which are:

a) Estrogen receptor (ER-α and ER-β) mutations,12,35

b) FSH receptor mutations (FSHr),61,62 associated with <1% POI cases.1,32, 60,63

c) LH receptor mutations (LHr)64 associated with <1 % POI cases.1,32,60,63

d) FOXL2 mutations: Occurs with either blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 (without POI) or BPES type 2 (with POI), known as POI-3.1,65,66

e) Steroidogenic factor 1 (NR5A1) mutation.12,35

f) CYP19A1 mutation.12,35,67,68

g) Inhibin A gene mutation associated with 5% of POI cases.60,69

h) NOBOX gene: Newborn ovary homeobox gene (NOBOX) plays role in initial phases of follicular maturation70 and is rarely associated with POI.71,72

Despite several genes shown to be associated with POI, the exact mechanism still remains uncertain.54,56,65,73

Autoimmune Factors

Autoimmunity is characterized by auto-reactive lymphocytosis, organ and non-organ-specific autoantibodies.74,75 It accounts for 4-30% of POI cases1,8,76,77,78,79,80,81,82 and is characterised by presence of antiovarian antibodies (AOAs), lymphocytic oophoritis on histopathological examination, in association with other autoimmune conditions.82,83,84,85,86 Exact mechanism of autoimmune POI remains obscure and may be due to genetic and or environmental factors that are responsible for initiating immune response.43,75,83,87,88 Important factors involved are: Major histocompatibility complex antigen (HLA), cytokines, cell-mediated immunity, antibodymediated immunity, etc.43,75,83,87,88

There are three main types of autoimmune POI: Adrenal autoimmune POI, non-adrenal autoimmune POI and isolated idiopathic POI.43,88,89 Autoimmune causes in pathogenesis of POI is characterised by presence of autoantibodies directed towards the ovarian tissue.84,90,91 These AOAs can be detected in the serum of affected females before clinical onset of POI.92 These antibodies bind to various steroid hormone-producing cells8,14, 82,93,94 like adrenal cortex cells, theca cells of ovary, placental syncytiotrophoblast cells, and are known as steroid cell antibodies (StCAs).82 They also bind to gonadotropins and their receptors,95,96,97 zona pellucid,98 oocyte,99 corpus luteum,84,100 and can act as markers of ovarian autoimmunity.82

Furthermore, it was observed that POI has strong association with autoimmune Addison’s disease. Around 60-87% cases of POI have Addison’s disease.14,82,90,93,101 There are two types of autoimmune polyendocrine syndromes (APS)5,74,75 strongly associated with POI. Type 1 APS [autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED)] characterized by combination of hypoparathyroidism, adrenal failure, and chronic mucocutaneous candidiasis. It is usually seen in children and is associated with POI in 60% cases presenting as primary amenorrhoea. Type II APS is characterised by autoimmune Addison’s disease with adrenal insufficiency and other autoimmune illnesses without hypoparathyroidism.5,74 It usually occurs between the third to fourth decades of life and is associated with POI in 25-40% cases.14,82,90,93,101 Other autoimmune conditions commonly associated with POI are: hypothyroidism,102,103,104 autoimmune adrenal insufficiency,105 hypoparathyroidism,79 type 1 diabetes mellitus, hypophysitis, autoimmune haemolytic anaemia, celiac disease, inflammatory bowel diseases, glomerulonephritis,5 Sjogren’s syndrome106 and myasthenia gravis.89

Iatrogenic

Iatrogenic causes for POI are increasing due to rise in incidence of various gynaecological cancers and their successful treatment.107,108 Oocyte is highly radiosensitive and responds to even 2 Gray dose of radiotherapy.43,109 Hence, an ovarian radiotherapy dose of ≥6 Gray results in ovarian insufficiency in almost all females over 40 years of age.110 Effect of radiotherapy on ovaries is dependent on dose, age, and radiation therapy field.43,111, 112 Chemotherapy also causes ovarian insufficiency but exact mechanisms are not clear; however, it is well known that chemotherapeutic agents affect granulosa cell functions and oocytes, ultimately causing ovarian insufficiency.43,113 Major predictive factors for development of ovarian insufficiency after chemotherapy are; age, class, dose of chemotherapeutic agent, concurrent use of radiotherapy, etc.43,108,114 It has been reported that use of alkylating agents (N-mustard, L-phenylalanine mustard, Chlorambucil, Busulfan, and Cyclophosphamide) are strongly associated with POI (40%).12

Infectious and Toxic agents

Till date there are no direct evidences available that suggest correlation between infections and POI, but studies report that Mumps oophoritis may be related to development of POI. True reason of post-oophritis ovarian failure is unknown.5,43,120 In vast majority of affected women, return of ovarian function occurs following recovery.18,43 Another infectious agent and its treatment that can be linked with POI is HIV infection.5,121 It has been reported that around 3.5% of females with POI have a history of infections like varicella, tuberculosis shigellosis, malaria and cytomegalovirus.7,43,80

Amongst the various toxins that are strongly associated with POI, smoking is one major toxin. It was found that there is an inverse relationship between number of cigarettes smoked per day and age at menopause.43,122 Smoking causes alteration of ovarian function, and leads to early menopause in female who smoke as compared to non-smokers.43,123

Other toxins that commonly affect ovarian functions and can lead to POI are: Polycyclic aromatic hydrocarbons (PaHs), toxic chemicals in tobacco, heavy metals, insecticides, plastics and industrial chemicals, but exact underlying mechanism is unclear.5,18

Clinical Course

Women with POI are typically observed with secondary amenorrhea/menopause, many a times preceded by irregular menstrual cycle at age <40 years.20,78 In few women with primary amenorrhea, the cause can be an underlying chromosomal abnormality.20 Other characteristic symptoms include hot flushes and night sweats20,124; these are mainly due to estrogen deficiency.118,125 Vaginal symptoms include dyspareunia and dryness, which can be distressing for women.125,126 In addition to these, women also suffer from sleep disturbances, mood swings, lack of concentration, depression, loss of libido, dry eyes,127 altered urinary frequency and lack of energy.117,125 These symptoms are usually transient and are mainly due to changes in ovarian functions (estrogen withdrawal rather than deficiency) that result from spontaneous onset of POI.125,128 Furthermore, it was observed that in women with surgically induced POI, symptoms are more severe and persistent.125

Diagnosis and Assessment

Diagnosis of POI can be easily made on clinical presentation, in woman <40 years of age with amenorrhea or oligomenorrhea of 4-6 months with two measurements of elevated FSH levels. Final diagnosis can be made on certain investigations which include125:

Gonadotropin Levels: Both FSH and LH are elevated in women with POI (hypergonadotropic amenorrhea). Elevated FSH levels are more significant than LH. High FSH levels are considered as gold standard for diagnosis of POI and values >25 U/L on two occasions, more than 4 weeks apart is indicative of ovarian insufficiency.125

Low Estrogen levels: Estradiol (E2) levels <50 pg/ml is typically observed in women with POI.78 Low estradiol levels in combination with high FSH and LH levels are diagnostic of POI.

Antimullerian Hormone (AMH): AMH is homodimeric glycoprotein consisting of two subunits,129,130 and is produced by granulosa cells of growing follicles.131 It regulates early follicular recruitment from primordial pool132 and is a good reflector of ovarian reserve.133,134,135 AMH levels are usually very low or undetectable in women with POI.136 Hence, AMH testing may become important diagnostic tool for assessment of ovarian reserve before and after chemotherapy in young women with pelvic cancers, before and after ovarian surgery, and for females at high risk of POI.137,138

Inhibin B: It is produced by granulosa cells of growing follicles,139 but its levels show significant variability between menstrual cycles. Hence, it is usually not recommended for diagnosis of POI.138

Once diagnosis of POI is made, other investigations include:

• Karyotyping and fragile X mental retardation 1 (FMR-1) premutation for genetic cause8

• Screening for autoimmune diseases like anti-adrenal, anti21-hydroxylase,8 anti-thyroid peroxidase, anti-thyroglobulin antibodies125 and AOA are recommended.

 

Future Fertility

Around 5-10% of women with POI conceive spontaneously due to fluctuations in ovarian functions.12,125,140 Till date no clear guidelines or drugs are available that can cause follicular development or increase fertility in women with POI.125 Various studies have tried to examine the role of ovulation inducing drugs, gonadotrophins, glucocorticoids, GnRH agonists and antagonists,141 but no clear advantage has been observed.12

However, fertility preservation techniques can be considered for women at risk of developing POI due to disease or its management. Considerably high rates of natural pregnancies were reported in such women who underwent fertility preservation pre-treatment.125,142 Another way of improving fertility in women with POI due to sterilizing surgeries is replacement of cryopreserved ovarian tissue, but this has been studied in very few cases.125,143

Recent advances have shown that oocyte donation is another option for women with POI desiring pregnancy.125 Such a successful pregnancy was first reported in 1984144 and since then it has become a ‘routine’ treatment.

Long-term Consequences of POI /Premature Menopause Bone Health

Estrogen is known for its beneficial effects on bone growth. It is responsible for increased bone remodelling and hence its deficiency is associated with bone loss, decreased mineral density and fracture risk, as seen after natural menopause.145,146 Net bone loss after menopause is usually 2-3% per year.147 Effect of estrogen deficiency on bone in women with POI is one of most clearly recognized adverse effects of POI. It usually remains asymptomatic for many years, until fragility fracture happens. Furthermore, depending on degree and duration of estrogen deficiency, women with POI develop reduced bone mineral density earlier as compared to normal females.148,149 An estimated 8-14% of women with POI suffer from osteoporosis148 as compared to normal females.150

Cardiovascular

Estrogen has cardio-protective effects and its early loss leads to increased risk of cardio-vascular mortality.138,151 Hence, women with POI are associated with high risk of cardio-vascular mortality.78,125,138,151 Various researches have proven that women with spontaneous POI suffer early onset coronary heart disease152 and are at increased risk of dying from coronary vascular diseases (CVDs).125,153,154 Furthermore it has been observed that women with pre-menopausal estrogen deficiency develop signs of endothelial dysfunction155 and premature atherosclerosis very early.125,156 It is well proven that estrogen plays an important role in ventricular contractile function,125,157 decreases insulin resistance125,158 and protects against lipid peroxidation, thereby playing an important role in cardio-protection.

Cognitive and Neurological Health

Few studies have observed the effects of POI on neurological health of women.125 POI, especially the one resulting from bilateral oophorectomy before onset of natural menopause, increases risk of cognitive impairment/dementia. This risk is found to be inversely proportional to the age at which oophorectomy is performed.12,159,160 Such women are also prone to develop Parkinsonism later in their life.12,159,160 Hence, it is very important to explain all possible detrimental effects on neurological health before planning for hysterectomy and/or oophorectomy in women <50 years, especially for prophylactic reasons.125

Sexual and Genito-urinary Functions

In most women with POI, sexual problems are due to physiological stress, or secondary reaction to emotional stress of diagnosis and infertility resulting from the disease.161 Furthermore, fertility treatment has unpredictable outcomes which leads to emotional stress and affect sexual functions in the long run.125,162 Hence, to hold POI as the sole cause for sexual dysfunction may be incorrect, also there are no direct evidences to evaluate effects of POI on sexuality.163

Most common symptoms are those related to estrogen deficiency, which include vasomotor symptoms, sleep disturbances, depression, fatigue, loss of libido, vaginal dryness and dyspareunia.125,164

Endocrine

Diseases Women with POI are prone to develop endocrine disorders later in their life. Around 20% with idiopathic POI develop hypothyroidism and most commonly Hashimoto thyroiditis.23 They also carry high risk of developing adrenal insufficiency.138

Future Perspectives

Most recent studies have shown the role of stem cells in the treatment of POI and have reported that oocytes can be generated from embryonic stem cells (ESCs).165,166 These ESCs are induced into primordial germ cells which are then aggregated with somatic cells of female embryonic gonads for fertilisation.166,167

Other pluripotent cells that have been studied for use include, mesenchymal stem cells (MSCs) used for repairing damaged ovaries induced by chemotherapy.168 Umbilical cord mesenchymal stem cells (UCMSCs) can also be used with advantage of little or no immune rejection.169 Adipose-derived stem cells (ADSCs) are another type of MSC that can be differentiated into multiple cell types.170

Bone marrow transplantation has also been studied for use in women with poor ovarian function after long-term chemotherapy.166,171 Hence, it is possible that with the latest research and advancement, ovarian aging may become reversible in the future, especially in women with POI.172

ACKNOWLEDGEMENT

I acknowledge and thank Dr. Namit Kant Singh for his advice and expertise.

CONFLICTS OF INTEREST

There are no conflicts of interest.

1. Beck-Peccoz P, Persani L. Premature ovarian failure. Orpha- net J Rare Dis. 2006; 1: 9. doi: 10.1186/1750-1172-1-9

2. Santoro N. Mechanisms of premature ovarian failure. Ann Endocrinol(Paris).2003;64(2):87-92. doi: AE-04-2003-64-2- 0003-4266-101019-ART06

3. Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am. 2003; 30(2): 287-302. doi: 10.1016/S0889-8545(03)00027-5

4. Jin M, Yu Y, Huang H. An update on primary ovarian insufficiency. Sci China Life Sci. 2012; 55(8): 677-686. doi: 10.1007/s11427-012-4355-2

5. Hernández-Angeles C, Castelo-Branco C. Early menopause: A hazard to a woman’s health. Indian J Med Res. 2016; 143(4): 420-427. doi: 10.4103/0971-5916.184283

6. Kumar M, Pathak D, Venkatesh S, Kriplani A, Ammini AC, Dada R. Chromosomal abnormalities & oxidative stress in women with premature ovarian failure (POF). Indian J Med Res. 2012; 135(1): 92-97. doi: 10.4103/0971-5916.93430

7. Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steril. 1990; 53(5): 804-810.

8. Nelson LM. Primary ovarian insufficiency. N Engl J Med. 2009; 360(6): 606-614. doi: 10.1056/NEJMcp0808697

9. Hewlett M, Mahalingaiah S. Update on primary ovarian in- sufficiency. Curr Opin Endocrinol Diabetes Obes. 2015; 22(6): 483-489. doi: 10.1097/MED.0000000000000206

10. Pouresmaeili F, Fazeli Z. Premature ovarian failure: A criti- cal condition in the reproductive potential with various genetic causes. Int J Fertil Steril. 2014; 8(1): 1-12. Website. http://ijfs. ir/journal/article/fulltext/3756.html. Accessed January 27, 2017.

11. Sükür YE, Kıvançlı IB, Ozmen B. Ovarian aging and pre- mature ovarian failure. J Turk Ger Gynecol Assoc. 2014; 15(3): 190-196. doi: 10.5152/jtgga.2014.0022

12. Fenton AJ. Premature ovarian insufficiency: Pathogenesis and management. J Midlife Health. 2015; 6(4): 147-153. doi: 10.4103/0976-7800.172292

13. Research on the menopause in the 1990s. Report of a WHO Scientific Group. World Health Organ Tech Rep Ser. 1996; 866: 1-107.

14. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oo- phoritis as a mechanism of follicular dysfunction in women with 46, XX spontaneous premature ovarian failure. Fertil Steril. 2005; 84(4): 958-965.

15. Little DT, Ward HR. Adolescent premature ovarian in- sufficiency following human papillomavirus vaccination: A case series seen in general practice. J Investig Med High Impact Case Rep. 2014; 2(4): 2324709614556129. doi: 10.1177/2324709614556129

16. Taylor AE. Systemic adversities of ovarian failure. J Soc Gynecol Investig. 2001; 8(1): S7-S9. Website. http://journals.sage- pub.com/doi/abs/10.1177/1071557601008001s03. Accessed January 27, 2017.

17. Snowdon DA, Kane RL, Beeson WL, et al. Is early natural menopause a biologic marker of health and aging? Am J Public Health. 1989; 79(6): 709-714. doi: 10.2105/AJPH.79.6.709

18. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005; 11(4): 391-410. doi: 10.1093/humupd/dmi012

19. Maiti GD. Premature ovarian failure: A chronic debilitating condition of womanhood. In: Talwar P, ed. Manual of Cytoge- netics in Reproductive Biology. London, UK: JP Medical Ltd; 2014: 119-120.

20. Zangmo R, Singh N, Sharma JB. Diminished ovarian reserve and premature ovarian failure: A review. IVF Lite. 2016; 3(2): 46-51. doi: 10.4103/2348-2907.192284

21. Luborsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition. Hum Reprod. 2003; 18(1): 199-206. doi: 10.1093/humrep/deg005

22. Skillern A, Rajkovic A. Recent developments in identify- ing genetic determinants of premature ovarian failure. Sex Dev. 2008; 2(4-5): 228-243. doi: 10.1159/000152039

23. Nelson LM, Covington SN, Rebar RW. An update: Sponta- neous premature ovarian failure is not an early menopause. Fer- til Steril. 2005; 83(5): 1327-1332.

24. 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. 2006; 98(13): 890- 896. doi: 10.1093/jnci/djj243

25. Panay N, Fenton A. Premature ovarian failure: A grow- ing concern. Climacteric. 2008; 11(1): 1-3. doi: 10.1080/1369 7130701878635

26. Murabito JM, Yang Q, Fox C, Wilson PW, Cupples LA. Her- itability of age at natural menopause in the framingham heart study. J Clin Endocrinol Metab. 2005; 90(6): 3427-3430. doi: 10.1210/jc.2005-0181

27. Picton HM, Harris SE, Muruvi W, Chambers EL. The in vitro growth and maturation of follicles. Reproduction. 2008; 136(6): 703-715. doi: 10.1530/REP-08-0290

28. Shelling AN. Premature ovarian failure. Reproduction. 2010; 140(5): 633-641. doi: 10.1530/REP-09-0567

29. Persani L, Rossetti R, Cacciatore C. Genes involved in hu- man premature ovarian failure. J Mol Endocrinol. 2010; 45(5): 257-279. doi: 10.1677/JME-10-0070

30. Morita Y, Tilly JL. Oocyte apoptosis: Like sand through an hourglass. Dev Biol. 1999; 213(1): 1-17. doi: 10.1006/dbio.1999.9344

31. Sullivan SD, Castrillon DH. Insights into primary ovarian insufficiency through genetically engineered mouse models. Se- min Reprod Med. 2011; 29(4): 283-298. doi: 10.1055/s-0031- 1280914

32. Fortuño C, Labarta E. Genetics of primary ovarian insuf- ficiency: A review. J Assist Reprod Genet. 2014; 31(12): 1573- 1585. doi: 10.1007/s10815-014-0342-9

33. Chapman C, Cree L, Shelling AN. The genetics of prema- ture ovarian failure: Current perspectives. Int J Womens Health. 2015; 7: 799-810. doi: 10.2147/IJWH.S64024

34. Jiao X, Qin C, Li J, et al. Cytogenetic analysis of 531 Chi- nese women with premature ovarian failure. Hum Reprod. 2012; 27(7): 2201-2207. doi: 10.1093/humrep/des104

35. Simpson JL. Genetic and phenotypic heterogeneity in ovar- ian failure: Overview of selected candidate genes. Ann N Y Acad Sci. 2008; 1135: 146-154. doi: 10.1196/annals.1429.019

36. Luisi S, Orlandini C, Regini C, Pizzo A, Vellucci F, Petraglia F. Premature ovarian insufficiency: From pathogenesis to clini- cal management. J Endocrinol Invest. 2015; 38(6): 597-603. doi: 10.1007/s40618-014-0231-1

37. Cox L, Liu JH. Primary ovarian insufficiency: An update. Int J Womens Health. 2014; 6: 235-243. doi: 10.2147/IJWH.S37636

38. Holland CM. 47, XXX in an adolescent with premature ovar- ian failure and autoimmune disease. J Pediatr Adolesc Gynecol. 2001; 14(2): 77-80. doi: 10.1016/S1083-3188(01)00075-4

39. Cordts EB, Christofolini DM, Dos Santos AA, Bianco B, Barbosa CP. Genetic aspects of premature ovarian failure: A literature review. Arch Gynecol Obstet. 2011; 283(3): 635-643. doi: 10.1007/s00404-010-1815-4

40. Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet J Rare Dis. 2010; 5: 8. doi: 10.1186/1750-1172-5-8

41. Nolin SL, Brown WT, Glicksman A, et al. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet. 2003; 72(2): 454-464. doi: 10.1086/367713

42. American College of Obstetricians and Gynecologists Com- mittee on Genetics. ACOG committee opinion. No. 338: Screening for fragile X syndrome. Obstet Gynecol. 2006; 107(6): 1483- 1485.

43. Ebrahimi M, Akbari Asbagh F. Pathogenesis and causes of premature ovarian failure: an update. Int J Fertil Steril. 2011; 5(2): 54-65. Website. http://ijfs.ir/journal/article/fulltext/2905. html. Accessed January 27, 2017.

44. Hagerman RJ, Hagerman PJ. The fragile X premutation: Into the phenotypic fold. Curr Opin Genet Dev. 2002; 12(3): 278- 283. doi: 10.1016/S0959-437X(02)00299-X

45. Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004; 27(7): 370-377. doi: 10.1016/j.tins.2004.04.009

46. Fiçicioglu C, Yildirim G, Attar R, Kumbak B, Yesildaglar N. The significance of the number of CGG repeats and autoantibod- ies in premature ovarian failure. Reprod Biomed Online. 2010; 20(6): 776-782. doi: 10.1016/j.rbmo.2010.02.011

47. Sullivan AK, Marcus M, Epstein MP, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod. 2005; 20(2): 402-412. doi: 10.1093/humrep/deh635

48. Wittenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premutation and reproduction. Fertil Steril. 2007; 87(3): 456-65. doi: 10.1016/j.fertnstert.2006.09.004

49. Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000; 97(3): 189-194. doi: 10.1002/1096-8628(200023)97:3<189::AID-AJMG1036> 3.0.CO;2-J

50. Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet. 2004; 74(5): 1051-1056. doi: 10.1086/420700

51. Van Esch H. The fragile X permutation: New insights and- clinical consequences. Eur J Med Genet. 2006; 49(1): 1-8. doi: 10.1016/j.ejmg.2005.11.001

52. Hundscheid RD, Sistermans EA, Thomas CM, et al. Imprint- ing effect in premature ovarian failure confined to paternally inherited fragile X premutations. Am J Hum Genet. 2000; 66(2): 413-418. doi: 10.1086/302774

53. McNatty KP, Moore LG, Hudson NL, et al. The oocyte and its role in regulating ovulation rate: A new paradigm in reproductive biology. Reproduction. 2004; 128(4): 379-386. Website. http://www.reproduction-online.org/content/128/4/379.short. Accessed January 27, 2017.

54. Shimasaki S, Moore RK, Otsuka F, Erickson GF. The bone morphogenetic protein system in mammalian reproduction. Endocr Rev. 2004; 25(1): 72-101. doi: 10.1210/er.2003-0007

55. Persani L, Rossetti R, Cacciatore C, Bonomi M. Primary Ovarian Insufficiency: X chromosome defects and autoimmunity. J Autoimmun. 2009; 33(1): 35-41. doi: 10.1016/j. jaut.2009.03.004

56. Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonado- tropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet. 2004; 75(1): 106-111. doi: 10.1086/422103

57. Laissue P, Christin-Maitre S, Touraine P, et al. Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur J Endocrinol. 2006; 154(5): 739-744. doi: 10.1530/eje.1.02135

58. Rossetti R, Di Pasquale E, Marozzi A, et al. BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein. Hum Mutat. 2009; 30(5): 804-810. doi: 10.1002/humu.20961

59. Wang B, Wen Q, Ni F, et al. Analyses of growth differen- tiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) mutation in chinese women with premature ovarian failure. Clin Endocrinol (Oxf). 2010; 72(1): 135-136. doi: 10.1111/j.1365-2265.2009.03613.x

60. Ohkubo M, Yabu T, Yamashita M, Shimizu A. Molecular cloning of two gonadotropin receptors in mummichog Fundulus heteroclitus and their gene expression during follicular development and maturation. Gen Comp Endocrinol. 2013; 184: 75-86. doi: 10.1016/j.ygcen.2012.12.019

61. Wei S, Chen S, Gong Z, et al. Alarelin active immunization influences expression levels of GnRHR, FSHR and LHR proteins in the ovary and enhances follicular development in ewes. Anim Sci J. 2013; 84(6): 466-475. doi: 10.1111/asj.12030

62. Beau I, Touraine P, Meduri G, et al. A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. J Clin Invest. 1998; 102(7): 1352-1359. doi: 10.1172/JCI3795

63. Touraine P, Beau I, Gougeon A, et al. New natural inactivating mutations of the follicle-stimulating hormone receptor: Cor- relations between receptor function and phenotype. Mol Endo crinol. 1999; 13(11): 1844-1854. doi: 10.1210/mend.13.11.0370

64. Pakarainen T, Zhang FP, Nurmi L, Poutanen M, Huhtani- emi I. Knockout of luteinizing hormone receptor abolishes the effects of follicle-stimulating hormone on preovulatory matura- tion and ovulation of mouse graafian follicles. Mol Endocrinol. 2005; 19(10): 2591-2602. doi: 10.1210/me.2005-0075

65. De Baere E, Beysen D, Oley C, et al. FOXL2 and BPES: Mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet. 2003; 72(2): 478-487. doi: 10.1086/346118

66. Mu W, Wen H, Li J, He F. Cloning and expression analy- sis of a HSP70 gene from Korean rockfish (Sebastes schlegeli). Fish Shellfish Immunol. 2013; 35(4): 1111-1121. doi: 10.1016/j. fsi.2013.07.022

67. Kohno S, Katsu Y, Urushitani H, Ohta Y, Iguchi T, Guillette LJ Jr. Potential contributions of heat shock proteins to tempera- ture-dependent sex determination in the American alligator. Sex Dev. 2010; 4(1-2): 73-87. doi: 10.1159/000260374

68. Kim H, Chun S, Gu BS, Ku SY, Kim SH, Kim JG. Rela- tionship between inhibin-α gene polymorphisms and premature ovarian failure in Korean women. Menopause. 2011; 18(11): 1232-1236. doi: 10.1097/gme.0b013e31821d6f7e

69. Chand AL, Harrison CA, Shelling AN. Inhibin and prema- ture ovarian failure. Hum Reprod Update. 2010; 16(1): 39-50. doi: 10.1093/humupd/dmp031

70. Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science. 2004; 305(5687): 1157- 1159. doi: 10.1126/science.1099755

71. Qin Y, Shi Y, Zhao Y, Carson SA, Simpson JL, Chen ZJ. Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure. Fertil Steril. 2009; 91(4 Suppl): 1507-1509. doi: 10.1016/j.fertnstert.2008.08.020

72. Wang J, Wang B, Song J, et al. New candidate gene POU5F1 associated with premature ovarian failure in Chinese patients. Reprod Biomed Online. 2011; 22(3): 312-316. doi: 10.1016/j.rbmo.2010.11.008

73. Achermann JC, Ozisik G, Meeks JJ, Jameson JL. Perspective: Genetic causes of human reproductive diseases. J Clin Endocri- nol Metab. 2002, 87(6): 2447-2454. doi: 10.1210/jc.87.6.2447

74. La Marca A, Brozzetti A, Sighinolfi G, Marzotti S, Volpe A, Falorni A. Primary ovarian insufficiency: Autoimmune causes. Curr Opin Obstet Gynecol. 2010; 22(4): 277-282. doi: 10.1097/ GCO.0b013e32833b6c70

75. Silva CA, Yamakami LY, Aikawa NE, Araujo DB, Car- valho JF, Bonfá E. Autoimmune primary ovarian insufficiency. Autoimmun Rev. 2014; 13(4-5): 427-430. doi: 10.1016/j.aut- rev.2014.01.003

76. Tuohy VK, Altuntas CZ. Autoimmunity and premature ovar- ian failure. Curr Opin Obstet Gynecol. 2007; 19(4): 366-369. doi: 10.1097/GCO.0b013e328220e90c

77. Meskhi A, Seif MW. Premature ovarian failure. Curr Opin Obstet Gynecol. 2006; 18(4): 418-426.

78. Rebar RW. Premature ovarian failure. Obstet Gynecol. 2009; 113(6): 1355-1363. doi: 10.1097/AOG.0b013e3181a66843

79. Dragojević-Dikić S, Marisavljević D, Mitrović A, Dikić S, Jovanović T, Janković-Raznatović S. An immunological insight into premature ovarian failure (POF). Autoimmun Rev. 2010; 9(11): 771-774. doi: 10.1016/j.autrev.2010.06.008

80. Panay N, Kalu E. Management of premature ovarian failure. Best Pract Res Clin Obstet Gynaecol. 2009; 23(1): 129-140. doi: 10.1016/j.bpobgyn.2008.10.008

81. Asbagh FA, Ebrahimi M. A case report of spontaneous pregnancy during hormonal replacement therapy for premature ovarian failure. Iran J Reprod Med. 2011; 9(1): 47-49. Website. http://pubmedcentralcanada.ca/pmcc/articles/PMC4212146/. Accessed January 27, 2017.

82. Ebrahimi M, Asbagh FA. The role of autoimmunity in pre- mature ovarian failure. Iran J Reprod Med. 2015; 13(8): 461- 472.

83. Khole V. Does ovarian autoimmunity play a role in the pathophysiology of premature ovarian insufficiency? J Midlife Health. 2010; 1(1): 9-13. doi: 10.4103/0976-7800.66986

84. Forges T, Monnier-Barbarino P, Faure GC, Béné MC. Au- toimmunity and antigenic targets in ovarian pathology. Hum Reprod Update. 2004; 10(2): 163-175. doi: 10.1093/humupd/dmh014

85. Pires ES, Meherji PK, Vaidya RR, Parikh FR, Ghosalkar MN, Khole VV. Specific and sensitive immunoassays detect multiple anti-ovarian antibodies in women with infertility. J Histochem Cytochem. 2007; 55(12): 1181-1190. Website. http:// journals.sagepub.com/doi/abs/10.1369/jhc.7A7259.2007. Accessed January 27, 2017.

86. Poppe K, Glinoer D, Tournaye H, et al. Thyroid autoimmu- nity and female infertility. Verh K Acad Geneeskd Belg. 2006; 68(5-6): 357-377. Website. http://europepmc.org/abstract/med/17313094. Accessed January 27, 2017.

87. Shamilova NN, Marchenko LA, Dolgushina NV, Zaletaev DV, Sukhikh GT. The role of genetic and autoimmune factors in premature ovarian failure. J Assist Reprod Genet. 2013; 30(5): 617-622. doi: 10.1007/s10815-013-9974-4

88. Carsote M, Valea A. Premature ovarian failure of autoim- mune causes. J Gynecol Neonatal Biol. 2015; 1(1): 1-2. Website. http://www.ommegaonline.org/article-details/Premature- ovarian-failure-of-autoimmune-causes/364. Accessed January 27, 2017.

89. Carp HJ, Selmi C, Shoenfeld Y. The autoimmune bases of in- fertility and pregnancy loss. J Autoimmun. 2012; 38(2-3): J266- J274. doi: 10.1016/j.jaut.2011.11.016

90. Cervera R, Balasch J. Bidirectional effects on autoimmunity and reproduction. Hum Reprod Update. 2008; 14(4): 359-366. doi: 10.1093/humupd/dmn013

91. Monnier-Barbarino P, Forges T, Faure GC, Béné MC. Gonadal antibodies interfering with female reproduction. Best Pract Res Clin Endocrinol Metab. 2005; 19(1): 135-148. doi: 10.1016/j.beem.2004.11.011

92. Luborsky J, Pong R. Pregnancy outcome and ovarian anti- bodies in infertility patients undergoing controlled ovarian hyperstimulation. Am J Reprod Immunol. 2000; 44(5): 261-265. doi: 10.1111/j.8755-8920.2000.440502.x

93. Reato G, Morlin L, Chen S, et al. Premature ovarian failure in patients with autoimmune Addison’s disease: Clinical, genetic, and immunological evaluation. J Clin Endocrinol Metab. 2011; 96(8): E1255-E1261. doi: 10.1210/jc.2011-0414

94. Dal Pra C, Chen S, Furmaniak J, et al. Autoantibodies to steroidogenic enzymes in patients with premature ovarian failure with and without Addison’s disease. Eur J Endocrinol. 2003; 148(5): 565-570. doi: 10.1530/eje.0.1480565

95. Chiauzzi VA, Bussmann L, Calvo JC, Sundblad V, Charreau EH. Circulating immunoglobulins that inhibit the binding of follicle-stimulating hormone to its receptor: A putative diagnostic role in resistant ovary syndrome? Clin Endocrinol (Oxf). 2004; 61(1): 46-54. doi: 10.1111/j.1365-2265.2004.02054.x

96. Ryan MM, Jones HR Jr. Myasthenia gravis and premature ovarian failure. Muscle Nerve. 2004; 30(2): 231-233. doi: 10.1002/mus.20067

97. Gobert B, Jolivet-Reynaud C, Dalbon P, et al. An immuno- reactive peptide of the FSH involved in autoimmune infertility. Biochem Biophys Res Commun. 2001; 289(4): 819-824. doi: 10.1006/bbrc.2001.6059

98. Koyama K, Hasegawa A. Premature ovarian failure syn drome may be induced by autoimmune reactions to zona pellucid proteins. J Reprod Endocrinol. 2006; 3: 94-97. Website. http://www.kup.at/journals/abbildungen/gross/6633.html. Accessed January 27, 2017.

99. Luborsky JL, Visintin I, Boyers S, Asari T, Caldwell B, DeCherney A. Ovarian antibodies detected by immobilized an- tigen immunoassay in patients with premature ovarian failure. J Clin Endocrinol Metab. 1990; 70(1): 69-75. doi: 10.1210/jcem- 70-1-69

100. Pasoto SG, Viana VS, Mendonca BB, Yoshinari NH, Bonfa E. Anti-corpus luteum antibody: A novel serological marker for ovarian dysfunction in systemic lupus erythematosus? J Rheumatol. 1999; 26(5): 1087-1093. Website. http://europepmc.org/ abstract/med/10332973. Accessed January 27, 2017.

101. Falorni A, Laureti S, Candeloro P, et al. Steroid-cell autoan- tibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity. Fertil Steril. 2002; 78(2): 270-279. doi: 10.1016/S0015-0282(02)03205-3

102. Welt CK. Autoimmune oophoritis in the adolescent. Ann N Y Acad Sci. 2008; 1135: 118-122. doi: 10.1196/annals.1429.006

103. Wémeau JL, Proust-Lemoine E, Ryndak A, Vanhove L. Thyroid autoimmunity and polyglandular endocrine syndromes. Hormones (Athens). 2013; 12(1): 39-45. Website. http://www. hormones.gr/pdf/HORMONES2013,39-45.pdf. Accessed January 27, 2017.

104. Abalovich M, Mitelberg L, Allami C, et al. Subclinical hypothyroidism and thyroid autoimmunity in women with infertility. Gynecol Endocrinol. 2007; 23(5): 279-283. doi: 10.1080/09513590701259542

105. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Auto-immune adrenal insufficiency and autoimmune polyendocrine syndromes: Autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002; 23(3): 327- 364. doi: 10.1210/edrv.23.3.0466

106. Euthymiopoulou K, Aletras AJ, Ravazoula P, et al. Anti- ovarian antibodies in primary Sjogren’s syndrome. Rheumatol Int. 2007; 27(12): 1149-1155. doi: 10.1007/s00296-007-0364-z

107. Sklar C. Maintenance of ovarian function and risk of pre- mature menopause related to cancer treatment. J Natl Cancer Inst Monogr. 2005; 34: 25-27. Website. http://citeseerx.ist.psu. edu/viewdoc/download?doi=10.1.1.589.3491&rep=rep1&type =pdf. Accessed January 27, 2017.

108. Rebar RW. Premature ovarian “failure” in the adolescent. Ann N Y Acad Sci. 2008; 1135: 138-145. doi: 10.1196/annals.1429.000

109. Wallace WHB, Thomson AB, Kelsey TW. The radiosensi- tivity of the human oocyte. Hum Reprod. 2003; 18(1): 117-121. doi: 10.1093/humrep/deg016

110. Ash P. The influence of radiation on fertility in man. Br J Radiol. 1980; 53(628): 271-278. doi: 10.1259/0007-1285-53- 628-271

111. Gracia CR, Sammel MD, Freeman E, et al. Impact of cancer therapies on ovarian reserve. Fertil Steril. 2012; 97(1): 134-140. doi: 10.1016/j.fertnstert.2011.10.040

112. Lie Fong S, Laven JS, Hakvoort-Cammel FG, et al. Assessment of ovarian reserve in adult childhood cancer survivors using anti-Müllerian hormone. Hum Reprod. 2009; 24(4): 982- 990. doi: 10.1093/humrep/den487

113. Oktem O, Oktay K. Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function. Cancer. 2007; 110(10): 2222-2229. doi: 10.1002/cncr.23071

114. Wallace WH. Oncofertility and preservation of reproductive capacity in children and young adults. Cancer. 2011; 117(10 Suppl): 2301-2310. doi: 10.1002/cncr.26045

115. Fenton A, Panay N. Does routine gynecological surgery contribute to an early menopause? Climacteric. 2012; 15(1): 1-2. doi: 10.3109/13697137.2012.647623

116. Kovacs P, Stangel JJ, Santoro NF, Lieman H. Successful pregnancy after transient ovarian failure following treatment of symptomatic leiomyomata. Fertil Steril. 2002; 77(6): 1292- 1295. doi: 10.1016/S0015-0282(02)03091-1

117. Conway GS. Premature ovarian failure. Br Med Bull. 2000; 56(3): 643-649. doi: 10.1258/0007142001903445

118. Longway M, Matthews CA. Resumption of ovarian function 20 years after chemotherapy-induced ovarian failure: A case report. Fertil Steril. 2009; 92(1): e17-e18. doi: 10.1016/j.fertnstert.2009.02.082

119. Wikström AM, Hovi L, Dunkel L, Saarinen-Pihkala UM. Restoration of ovarian function after chemotherapy for osteosarcoma. Arch Dis Child. 2003; 88(5): 428-431. doi: 10.1136/adc.88.5.428

120. Wang H, Chen H, Qin Y, et al. Risks associated with pre- mature ovarian failure in Han Chinese women. Reprod Biomed Online. 2015; 30(4): 401-407. doi: 10.1016/j.rbmo.2014.12.013

121. Ohl J, Partisani M, Demangeat C, Binder-Foucard F, Nisand I, Lang JM. [Alterations of ovarian reserve tests in Human Im- munodeficiency Virus (HIV)-infected women]. Gynecol Obstet Fertil. 2010; 38(5): 313-317. doi: 10.1016/j.gyobfe.2009.07.019

122. Chang SH, Kim CS, Lee KS, et al. Premenopausal factors influencing premature ovarian failure and early menopause. Maturitas. 2007; 58(1): 19-30. doi: 10.1016/j.maturitas.2007.04.001

123. Di Prospero F, Luzi S, Iacopini Z. Cigarette smoking dam- ages women’s, reproductive life. Reprod Biomed Online. 2004; 8(2): 246-247. doi: 10.1016/S1472-6483(10)60525-1

124. Panay N, Maclaran K, Nicopollous J, Horner E, Domoney C. Findings from the West London Menopause and PMS Centre POF Database. In: Proceedings of the 32nd British Belfast, Northern Ireland, UK: International congress of obstetrics and gynaecology; 2010: 20-23.

125. European Society for Human Reproduction and Embryol- ogy (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): 926-937. doi: 10.1093/humrep/dew027

126. Davis SR, Jane F. Sex and perimenopause. Aust Fam Physician. 2011; 40(5): 274-278. Website. http://search.proquest. com/openview/ca481b530410c94899ccd04ec868a360/1?pq- origsite=gscholar&cbl=33668. Accessed January 27, 2017.

127. Smith JA, Vitale S, Reed GF, et al. Dry eye signs and symp- toms in women with premature ovarian failure. Arch Ophthal- mol. 2004; 122(2): 151-156. doi: 10.1001/archopht.122.2.151

128. Knauff EA, Eijkemans MJ, Lambalk CB, et al. Anti-Mulle- rian hormone, inhibin B, and antral follicle count in young women with ovarian failure. J Clin Endocrinol Metab. 2009; 94(3): 786-792. doi: 10.1210/jc.2008-1818

129. Kumar N, Singh AK. Role of Antimüllerian hormone in gy- necology: A review of literature. Int J Infertil Fetal Med. 2015; 6(2): 51-61. doi: 10.5005/jp-journals-10016-1102

130. Cate RL, Mattaliano RJ, Hession C, et al. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell. 1986; 45(5): 685-698. doi: 10.1016/0092-8674(86)90783-X

131. Durlinger AL, Gruijters MJ, Kramer P, et al. Anti-Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology. 2002; 143(3): 1076-1084. doi: 10.1210/endo.143.3.8691

132. Durlinger AL, Kramer P, Karels B, et al. Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary. Endocrinology. 1999; 140(12): 5789-5796. doi: 10.1210/ endo.140.12.7204

133. Nardo LG, Christodoulou D, Gould D, Roberts SA, Fitzger- ald CT, Laing I. Anti-Müllerian hormone levels and antral follicle count in women enrolled in in-vitro fertilization cycles: Relationship to lifestyle factors, chronological age and reproductive history. Gynecol Endocrinol. 2007; 23(8): 486-493. doi: 10.1080/09513590701532815

134. van Disseldorp J, Lambalk CB, Kwee J, et al. Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts. Hum Reprod. 2010; 25(1): 221-227. doi: 10.1093/humrep/dep366

135. Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-Müllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metab. 2004; 89(1): 318-323. doi: 10.1210/jc.2003-030932

136. Visser JA, Schipper I, Laven JS, Themmen AP. Anti-Mül- lerian hormone: An ovarian reserve marker in primary ovar- ian insufficiency. Nat Rev Endocrinol. 2012; 8(6): 331-41. doi: 10.1038/nrendo.2011.224

137. Nelson SM. Biomarkers of ovarian response: current and future applications. Fertil Steril. 2013; 99(4): 963-969. doi: 10.1016/j.fertnstert.2012.11.051

138. Committee opinion no. 605: Primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014; 124(1): 193-197. doi: 10.1097/01.aog.0000451757.51964.98

139. Halder A, Fauzdar A, Ghosh M, Kumar A. Serum inhibin B: A direct and precise marker of ovarian function. J Clin Diagn Res. 2007: 1: 131-137. Website. http://www.jcdr.net/back_is- sues.asp?issn=0973-709x&year=2007&month=June&vo- lume=1&issue=3&page=131-137&id=69. Accessed January 27, 2017.

140. De Caro JJ, Dominguez C, Sherman SL. Reproductive health of adolescent girls who carry the FMR1 premutation: Expected phenotype based on current knowledge of fragile X-associated primary ovarian insufficiency. Ann N Y Acad Sci. 2008; 1135: 99-111. doi: 10.1196/annals.1429.029

141. Ben-Nagi J, Panay N. Premature ovarian insufficiency: How to improve reproductive outcome? Climacteric. 2014; 17(3): 242-246. doi: 10.3109/13697137.2013.860115

142. Schmidt KT, Nyboe Andersen A, Greve T, Ernst E, Loft A, Yding Andersen C. Fertility in cancer patients after cryopreser- vation of one ovary. Reprod Biomed Online. 2013; 26(3): 272- 279. doi: 10.1016/j.rbmo.2012.12.001

143. Donnez J, Dolmans MM, Pellicer A, et al. Restoration of ovarian activity and pregnancy after transplantation of cryo- preserved ovarian tissue: A review of 60 cases of reimplantation. Fertil Steril. 2013; 99(6): 1503-1513. doi: 10.1016/j.fertn- stert.2013.03.030

144. Lutjen P, Trounson A, Leeton J, Findlay J, Wood C, Renou P. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature. 1984; 307(5947): 174-175. doi: 10.1038/307174a0

145. Sirola J, Kröger H, Honkanen R, et al. Smoking may impair the bone protective effects of nutritional calcium: A population- based approach. J Bone Miner Res. 2003; 18(6): 1036-1042. doi: 10.1359/jbmr.2003.18.6.1036

146. Banks E, Reeves GK, Beral V,Balk will A,Liu B,Roddam A. Million Women Study Collaborators. Hip fracture incidence in relation to age, menopausal status, and age at menopause: Prospective analysis. PLoS Med. 2009; 6(11): e1000181. doi: 10.1371/journal.pmed.1000181

147. Manolagas SC, O’Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol. 2013; 9(12): 699-712. doi: 10.1038/nren-do.2013.179

148. Bachelot A, Rouxel A, Massin N, et al. POF-GIS Study Group. Phenotyping and genetic studies of 357 consecutive pa- tients presenting with premature ovarian failure. Eur J Endocri- nol. 2009; 161(1): 179-1487. doi: 10.1530/EJE-09-0231

149. Freriks K, Timmermans J, Beerendonk CC, et al. Standard- ized multidisciplinary evaluation yields significant previously undiagnosed morbidity in adult women with turner syndrome. J Clin Endocrinol Metab. 2011; 96(9): E1517-E1526. doi: 10.1210/jc.2011-0346

150. Popat VB, Calis KA, Vanderhoof VH, et al. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 2009; 94(7): 2277-2283. doi: 10.1210/jc.2008-1878

151. van der Schouw YT, van der Graaf Y, Steyerberg EW, Ei- jkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet. 1996; 347(9003): 714-718. doi: 10.1016/S0140-6736(96)90075-6

152. Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: A meta-analysis. Menopause. 2006; 13(2): 265-279. doi: 10.1097/01.gme.0000218683.97338.ea

153. Baba Y, Ishikawa S, Amagi Y, Kayaba K, Gotoh T, Kajii E. Premature menopause is associated with increased risk of ce- rebral infarction in Japanese women. Menopause. 2010; 17(3): 506-510. doi: 10.1097/gme.0b013e3181c7dd41

154. Gallagher LG, Davis LB, Ray RM, et al. Reproductive his- tory and mortality from cardiovascular disease among women textile workers in shanghai, china. Int J Epidemiol. 2011; 40(6):1510-1518. doi: 10.1093/ije/dyr134

155.  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(8): 3907-3913. doi: 10.1210/jc.2004-0015

156. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis pro- gression. Menopause. 2007; 14(3 Pt 1): 373-384. doi: 10.1097/ GME.0b013e31803c764d

157. RenJ,HintzKK,RougheadZK,etal.Impactofestro- gen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation. Am J Physiol Heart Circ Physiol. 2003; 284(5): H1800-H1807. Website. https://pubag. nal.usda.gov/pubag/article.xhtml?id=46686. Accessed January 27, 2017.

158. Sumino H, Ichikawa S, Itoh H, et al. Hormone replacement therapy decreases insulin resistance and lipid metabolism in Japanese postmenopausal women with impaired and normal glucose tolerance. Horm Res. 2003; 60(3): 134-142. doi: 10.1159/000072525

159. Rocca WA, Shuster LT, Grossardt BR, et al. Long-term effects of bilateral oophorectomy on brain aging: Unanswered questions from the mayo clinic cohort study of oophorectomy and aging. Womens Health (Lond). 2009; 5(1): 39-48. doi: 10.2217/17455057.5.1.39

160. Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature menopause or early menopause: Long- term health consequences. Maturitas. 2010; 65(2): 161. doi: 10.1016/j.maturitas.2009.08.003

161. King RB. Subfecundity and anxiety in a nationally rep-resentative sample. Soc Sci Med. 2003; 56(4): 739-751. doi: 10.1016/S0277-9536(02)00069-2

162. Slade P, Emery J, Lieberman BA. A prospective, longitudinal study of emotions and relationships in in-vitro fertilization treatment. Hum Reprod. 1997; 12(1): 183-190. doi: 10.1093/humrep/12.1.183

163. Graziottin A, Basson R. Sexual dysfunction in women with premature menopause. Menopause. 2004; 11(6 Pt 2): 766-777. doi: 10.1097/01.gme.0000139926.02689.a1

164. NIH State-of-the-Science Conference Statement on management of menopause-related symptoms. NIH Consens State Sci Statements. 2005; 22(1): 1-38.

165. Nicholas CR, Haston KM, Grewall AK, Longacre TA, Reijo Pera RA. Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for fe- male infertility. Hum Mol Genet. 2009; 18(22): 4376-4389. doi: 10.1093/hmg/ddp393

166. Dan S, Haibo L, Hong L. Pathogenesis and stem cell ther- apy for premature ovarian failure. OA Stem Cells. 2014; 2(1): 4. Website. http://ifctp.org/download/Embryonic%20Stem%20 Cells/ESC%20for%20Fertility/Pathogenesis%20and%20 stem%20cell%20therapy%20for%20premature%20ovarian.pdf. Accessed January 27, 2017.

167. Hayashi K, Saitou M. Generation of eggs from mouse embryonic stem cells and induced pluripotent stem cells. Nat Pro toc. 2013; 8(8): 1513-1524. doi: 10.1038/nprot.2013.090

168. Kilic S, Pinarli F, Ozogul C, Tasdemir N, Naz Sarac G, Delibasi T. Protection from cyclophosphamide-induced ovar- ian damage with bone marrow-derived mesenchymal stem cells during puberty. Gynecol Endocrinol. 2014; 30(2): 135-140. doi: 10.3109/09513590.2013.860127

169. Tipnis S, Viswanathan C, Majumdar AS. Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: Role of B7-H1 and IDO. Immunol Cell Biol. 2010; 88(8): 795-806. doi: 10.1038/icb.2010.47

170. Varma MJ, Breuls RG, Schouten TE, et al. Phenotypical and functional characterization of freshly isolated adipose tissue-derived stem cells. Stem Cells Dev. 2007; 16(1): 91-104. doi: 10.1089/scd.2006.0026

171. Lee HJ, Selesniemi K, Niikura Y, et al. Bone marrow trans- plantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol. 2007; 25(22): 3198- 3204. doi: 10.1200/JCO.2006.10.3028

172. White YA, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat Med. 2012; 18(3): 413-421. doi: 10.1038/nm.2669

LATEST ARTICLES

LATEST ARTICLES