P re m a t u re Ov a r i a n F a i l u re Clinical Presentation and Treatment Ertug Kovanci,

MD*,

Amy K. Schutt,

MD

KEYWORDS  Infertility  Estrogen therapy  Ovarian failure  Autoimmune disorders  Heart disease  Osteoporosis KEY POINTS  Long-term health consequences, including psychological distress, infertility, osteoporosis, heart disease, autoimmune disorders, and increased mortality, have a significant impact on the quality of life for the woman diagnosed with premature ovarian failure.  Initiation of hormone replacement therapy (HRT) should be initiated immediately without considering the Women’s Health Initiative findings.  Donor oocyte in vitro fertilization has high pregnancy rates.

INTRODUCTION AND TERMINOLOGY

Premature ovarian failure (POF) is defined as hypergonadotropic hypogonadism with the cessation of menses before age 40. About 1% to 3% of women experience POF before age 40.1,2 The incidence is lower in younger women. A follicle stimulating hormone (FSH) concentration greater than 20 to 40 mIU/mL in the presence of amenorrhea has been proposed to define ovarian failure.3 The presumption of ovarian failure is evidenced by the association between decreased natural fecundity and lowered assisted reproductive technology success rates with increased FSH concentrations and increased age. When the FSH concentrations are greater than 12 to 15 mIU/mL in women who are less than the age of 40 years with regular cycles, the ovaries are unlikely to respond to the stimulating agents, such as human menopausal gonadotropins and recombinant FSH. On the other hand, some women who are diagnosed with POF may become pregnant spontaneously albeit the likelihood is low. Therefore, the term “primary ovarian insufficiency” has been proposed as an alternative to POF by some investigators.4,5 This new term sounds like it covers different spectrums of the disorder and, thus, may be more appropriate for clinical use. However, the term

Authors have no conflict of interests to disclose. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, 6651 Main Street, Suite E350, Houston, TX 77030, USA * Corresponding author. E-mail address: [email protected] Obstet Gynecol Clin N Am 42 (2015) 153–161 http://dx.doi.org/10.1016/j.ogc.2014.10.004 obgyn.theclinics.com 0889-8545/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

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primary ovarian insufficiency may lead to phenotypic heterogeneity in translational studies. Recruitment of heterogeneous study populations may prevent finding significant associations between the disorder and the genotype. Even the current term POF includes a heterogeneous group of women as the various clinical presentations suggest. Manifestations of POF, defined as an FSH level greater than 40 mIU/mL with amenorrhea before age 40, include primary amenorrhea, secondary amenorrhea, presence or absence of autoimmune disorders, and association with chromosomal abnormalities such as Turner syndrome, all of which imply different causes. Moreover, the authors do not think insufficiency has a better connotation than failure, and these 2 words are actually synonyms. To prevent unnecessary confusion in the literature, the continued use of the term POF is suggested. CAUSE

It is well known that X chromosome abnormalities are the underlying cause in some cases of POF. The most common of these abnormalities is 45,X or Turner syndrome, which affects 1 in 2500 female newborns worldwide.6 It is thought that 75% or more of conceptions affected by Turner syndrome result in spontaneous abortion.7 Turner syndrome is characterized clinically by short stature, cardiovascular anomalies (especially coarctation of the aorta and aortic valvular abnormalities), webbed neck, lymphedema, and POF. In addition to Turner syndrome, other X chromosome aberrations, such as deletions of the short or long arm of the X chromosome, have been shown to be associated with POF.6 These deletions show variable phenotype depending on the location of the deletion. Proximal deletions of Xq are associated with primary amenorrhea especially if these originate more proximal than Xq21.6 Similarly, the amount of remaining Xp also affects the phenotype.6 The numerous cases of X chromosome abnormalities and POF have led to the identification of a “critical region” at Xq13.3-Xq27. Several candidate genes in this region have been suggested; however, the exact contributors remain elusive. Autosomal chromosomal abnormalities and balanced autosomal reciprocal translocations can also be associated with POF. Necropsy examinations on fetuses with trisomy 13 and 18 revealed findings consistent with ovarian dysgenesis.8 Numerous autosomal genes are known to affect ovarian development, and translocations involving a sex chromosome and autosome may affect autosomal gene expression, and/or meiosis I progression.8 POF can also be part of various phenotypic abnormalities that are seen in well-defined Mendelian disorders. Autoimmune polyendocrine syndrome (APS) type 1 and 2 show multiple endocrine organ failures including adrenal insufficiency, hypoparathyroidism, hypothyroidism, type 1 diabetes mellitus, and ovarian failure. APS type 1 is caused by mutations in the AIRE gene.9 Perrault syndrome is an autosomal-recessive disorder involving POF and neurosensory deafness. The connexin 37 gene is an attractive candidate for this disorder because the connexin gene family is responsible for many congenital forms of deafness, and the null mice for connexin 37 develop ovarian failure.10 Another Mendelian disorder associated with POF is ataxia telangiectasia. It involves cerebellar ataxia, telangiectesias, immunodeficiency, genomic instability, and malignancy.11 The gene that has been found to be mutated in patients with ataxi-telangiectesia is named the ATM gene.12 Women with type I blepharophimosis, ptosis, epicanthus inversus syndrome can present with POF.13 FOXL2 mutations have been identified in these women. Fragile X syndrome is of note because not only does it have an intricate genetic origin but also it is one of the

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most common causes of POF. Fragile X premutation carriers are at risk for POF; however, women with the full mutation are not at risk. The incidence of fragile X premutations (carrier state) in women with POF was found to be between 3% and 12% depending on the family history.14 On the other hand, approximately 20% of the fragile X carriers develop POF.15 More than 100 mouse models involving gonosomal or autosomal genes exhibit ovarian failure.8 Best known models include growth differentiating factor 9, newborn ovary homeobox, G protein-coupled receptor, and factor in germline a knock-out animals, all preferentially expressed in the oocytes. Perturbations of somatic genes can also cause POF because these genes are involved in human ovarian development and function. Examples include follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR). In summary, a large group of candidate genes for idiopathic POF have been derived based on the genes that are deleted or located in the autosomal or sex chromosomal breakpoints, animal models of ovarian failure, genes involved in syndromic POF cases, and genes involved in ovarian development and function. However, studies that investigated the perturbations of candidate genes in women with idiopathic POF in different ethnic populations yielded no association or weak associations with low incidence. It is estimated that the cause of 90% of the primary POF cases still remains unknown.16 It is clear that POF is a genetically highly heterogeneous disorder, because mouse knockouts in more than 100 different genes prematurely lose ovarian function. These results likely explain the low yields observed in clinical studies with single candidate gene approaches. Recently, genome-wide association studies (GWAS) have focused on age at menopause and POF. GWAS were aimed at finding associations between genotype markers and phenotype in very large patient and control populations. Several GWAS have been conducted in various ethnic populations to identify the genotypes associated with age at menopause and POF.17–19 The quest to identify the genetic mutation leading to POF continues. DIAGNOSTIC WORKUP

Diagnostic workup is usually triggered by the absence of menarche, the cessation of menses, or infertility. Clinical presentation dictates the type of workup necessary (Box 1). A physical examination to rule out other reproductive disorders is indicated. It should include a thorough general and pelvic examination, including the breast, axillary hair, and pubic hair development. A pelvic ultrasound may be necessary if an adequate pelvic examination cannot be performed. Primary amenorrhea can be caused by various congenital disorders, such as Mullerian agenesis, androgen insensitivity, and XY gonadal dysgenesis or Swyer syndrome. However, the most common

Box 1 Most commonly performed initial workup Serum FSH Karyotype Fragile X carrier screening Serum TSH Dual energy x-ray absorptiometry scan

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reason for primary amenorrhea with hypergonadotropic hypogonadism is 45,X, or Turner syndrome. All women with primary amenorrhea should undergo serum FSH measurement. If the FSH level is found to be elevated, karyotyping is indicated to determine if Turner syndrome or a rare male pseudohermaphroditism syndrome is present. Karyotyping also allows the identification of other chromosomal aberrations such as X chromosome deletions and autosomal translocations. Secondary amenorrhea should prompt urinary or serum pregnancy testing. After an unexpected pregnancy is ruled out, prolactin and thyroid stimulating hormone (TSH) levels should be determined to exclude hyperprolactinemia and thyroid disorders, which frequently cause menstrual abnormalities. If prolactin and TSH levels are within normal limits, progestin challenge test is performed to produce withdrawal bleeding. In the absence of withdrawal bleeding, which indicates hypoestrogenism or a reproductive tract outlet problem, the FSH level should be determined. Alternatively, an FSH level may be included in the initial workup if clinically indicated based on the presentation. Classically, 2 FSH levels greater than 40 mIU/mL, performed 1 month apart, indicate POF. More recently, an anti-Mu¨llerian hormone (AMH) concentration less than 1.0 ng/mL has been shown to reflect a diminished ovarian reserve. However, this should not be confused with POF because even women with undetectable AMH levels frequently continue to have regular periods and FSH concentrations less than 15 mIU/mL. A high FSH level continues to be the preferred diagnostic test. On the other hand, very low levels of AMH may be the first sign of impending POF and could be used as an early screening test. More research is needed to determine the predictive value of very low AMH levels. Once the POF diagnosis is established, karyotyping may be performed to rule out structural autosomal and sex chromosomal abnormalities as well as Turner syndrome and mosaic Turner syndrome (45,X/46,XX). Many experts suggest checking the karyotype in women who are younger and have never been pregnant. The value of chromosome analysis is diminished in women who are older than 30 to 35 years old and have had a child. On the other hand, fragile X carrier screening is recommended to all women with POF by the American College of Obstetricians and Gynecologists.20 The CGG repeat numbers between 55 and 200 in the FMR gene increase the risk for POF.20 CLINICAL PICTURE

The diagnosis of POF can be devastating for patients. POF is a disorder that will have long-term effects on reproductive capabilities as well as on general health (Box 2). Women with POF report more anxiety, depression, and psychological distress than

Box 2 Long-term consequences of premature ovarian failure Infertility Psychological distress and depression Decreased sexual and general well-being Autoimmune disorders Osteoporosis Ischemic heart disease Increased risk for mortality

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controls.21 Therefore, supportive therapy and psychological counseling may be helpful, but is overlooked frequently. Clinical consequences of hypoestrogenemia such as osteoporosis and genital atrophy may have a significant impact on the quality of life. Bone mass loss develops rapidly after ovarian failure. Vaginal atrophy manifests with dryness, irritation, and dyspareunia. Coupled with emotional distress because of fertility concerns, genital atrophy may easily strain the patient’s personal life. Women with POF are less satisfied with their sexual lives and complain more frequently about diminished general and sexual well-being than controls.21 Their androgen concentrations are also decreased significantly, which contributed to sexual dysfunction. Various autoimmune disorders are associated with POF. Autoimmune hypothyroidism, adrenal insufficiency, type 1 diabetes mellitus, pernicious anemia, and hypoparathyroidism have been reported in the literature (Box 3). Hypothyroidism is the most common autoimmune disorder in association with POF. The incidence of hypothyroidism in women with POF is about 8%.22 Other autoimmune disorders are relatively uncommon. The incidence of diabetes mellitus has been shown to be 2.5%. Although clinically symptomatic adrenal insufficiency is rare, it has been reported that 3.2% of women with POF have adrenal antibodies to the 21-hydroxylase enzyme.22 Future pregnancy with autologous oocytes is considered impossible in women with primary amenorrhea and Turner syndrome. On the other hand, about 5% to 10% of women with secondary amenorrhea and hypergonadotropic hypogonadism may ovulate spontaneously and become pregnant. However, most women with POF have a low likelihood of a spontaneous pregnancy. It is almost impossible to predict which women will ovulate and become pregnant. The only successful fertility treatment option is in vitro fertilization (IVF) using donated oocytes. Women with Turner syndrome are not recommended to become pregnant even with donor oocytes because of the high rates of mortality during pregnancy resulting from aortic aneurysm rupture. It has been shown that the risk of aortic aneurysm rupture cannot be determined based on the size of the aortic root dilatation.23 Pregnancy should be avoided in Turner syndrome. Observational studies suggest cardiovascular disease risk is increased in women with POF.24 A secondary analysis of the Danish Nurse Cohort study reported a 2.1fold increased risk for ischemic heart disease in women who experienced menopause before age 40 compared women with age of menopause greater than 45.25 Hormone replacement therapy (HRT) decreased this risk in women whose POF was due to the surgical removal of bilateral ovaries. This increased risk may be partly due to impaired endothelial function, which can also be reversed with HRT.26

Box 3 Autoimmune diseases associated with premature ovarian failure Hypothyroidism Adrenal insufficiency Type 1 diabetes mellitus Pernicious anemia Hypoparathyroidism Myasthenia gravis Rheumatoid arthritis Systemic lupus erythematosus

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Overall mortality was also found to be increased in women with POF.27 A Norwegian study including about 20,000 women with a 37-year follow-up showed that women who had menopause before age 40 experienced the highest rates of mortality.2 Ischemic heart disease, stroke, and cancers were the most common causes for mortality in this study. MANAGEMENT

Prevention of consequences of hypoestrogenemia must be the first goal of the management. These women should be offered HRT as soon as POF is diagnosed. The form of HRT can be selected based on the patient’s preference. HRT regiments that are used in postmenopausal women can be considered. However, women with POF may require higher doses of estrogen than postmenopausal women. Oral contraceptives (OCPs) present a good alternative to postmenopausal HRT regiments. OCPs generally have 2-fold to 4-fold higher estrogen content than postmenopausal HRT regiments. Another benefit of OCPs is that many of the peers of these patients will be taking OCPs for birth control, possibly increasing patients’ satisfaction with the treatment. The counseling regarding the risks of the HRT in these patients should be similar to the counseling of other reproductive-aged women who are interested in hormonal contraception. The findings of the Women’s Health Initiative (WHI) study, such as increased risk for breast cancer, heart attack, and stroke, should not be considered relevant to these women. It is important to remember that none of the postmenopausal HRT studies included women who were younger than the age of 40.28,29 The average age was 63 in both arms of the WHI study. If women with POF consider staying on HRT after age 50, then they can be counseled appropriately based on the findings of the WHI and other similar studies in postmenopausal women. The route of the estrogen therapy, on the other hand, may affect the side-effect profile. For patients who are at risk for thromboembolic events such as smokers, the transdermal route may be preferred. The ESTHER study demonstrated that the transdermal estrogen therapy does not increase the risk of deep venous thrombosis (DVT).30 The same study also showed that certain types of progestins can increase the DVT risk, whereas progesterone has no effect on the DVT risk. Furthermore, the transdermal estrogen therapy in postmenopausal women did not increase the stroke risk in the British nested stroke study.31 Taken together, all these studies suggest transdermal estrogen therapy combined with oral micronized progesterone may have a better side-effect profile than oral estrogens combined with progestins. The authors’ preferred estrogen therapy regiment in women who are not interested in taking OCPs is transdermal estrogen patch or cream combined with cyclical oral micronized progesterone every 1 to 3 months. Topical estrogen supplementation should be used in women with POF who continue to have vaginal complaints despite the systemic HRT. Vaginal atrophy may be a continued concern even on systemic therapy in women with primary amenorrhea. A topical approach is also an excellent option for progesterone supplementation because vaginal progesterone cream and pills are easily absorbed and yield very high tissue levels in the uterus. It has been estimated the tissue levels of progesterone are 4 times higher compared with intramuscular or oral use. Vaginal progesterone pills are less messy compared with the cream. Thus, it is preferred for HRT in women with POF. However, the cost can be a problem for vaginal progesterone medications. A new oral medication, ospimefene, is a selective estrogen receptor modulator with estrogenic effects on the vaginal mucosa in clinical studies and antiestrogenic effects on the breast in animal studies.32,33 Ospimefene can be considered for women with

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dyspareunia due to atrophic changes of the vagina if patients are adverse to vaginal treatments. Osteoporosis is serious concern as the maximum bone density is reached in the mid-twenties. Prompt diagnosis and treatment are crucial to achieve the maximum bone health. Bone density measurement should be considered, especially for women whose diagnosis was delayed, thus, who did not receive HRT for a long period of time. Calcium and vitamin D supplementation is recommended. Daily requirement for Calcium is 1000 to 1500 mg for reproductive-aged women, most of which can be obtained through diet if encouraged. Many women are found to have low vitamin D levels in today’s society. The authors recommend routinely checking vitamin D levels. Recommended daily supplementation dose for postmenopausal women is 800 IU. However, if the vitamin D levels are found to be low, high doses up to 50,000 units weekly can be administered. If osteoporosis is detected, an antiresorptive therapy such as bisphosphonates should be considered in women who are already on estrogen therapy. There are newer antiresorptive therapies such Denosumab. Alendronate, Risedronate, Zoledronic acid, and Denosumab are considered first-line therapy.34 Ibandronate is a second-line agent, and Raloxifene is considered a second-line or third-line agent. Teriparatide, a parathyroid hormone analogue, is recommended for patients with very high fracture risk or for failed bisphosphonate therapy. Calcitonin should be used as the last line of therapy. However, most of the data and recommendations are for postmenopausal women, which are not as robust for younger women with POF. Data from premenopausal women with osteoporosis due to other chronic medical problems such as systemic lupus erythematosus, cystic fibrosis, or chronic kidney disease suggest medical treatment with various agents may be beneficial. Screening for other autoimmune disorders seems to be prudent. TSH is probably the single most important test for this purpose. Fasting blood glucose, complete blood count, serum calcium, and adrenal antibodies to the 21-hydroxylase enzyme may be helpful in the identification of other autoimmune disorders. The authors routinely screen for TSH abnormalities and selectively screen for other autoimmune disorders based on presentation after taking a careful history and physical examination. Measurement of antiovarian antibodies is not helpful because they have no clinical meaning nor do they change the management. Thus, it is not recommended to obtain antiovarian antibody levels. Various clinical studies failed to show significant benefit from various fertility treatments such estrogen priming followed by IVF except for occasional case reports. Ovarian biopsy via laparoscopy or transvaginal ultrasound examinations to determine follicular activity has not been shown to correlate with pregnancy or infertility treatment success. Therefore, routine clinical use of these methods is not recommended. Estrogen pretreatment and various ovarian stimulation protocols involving high-dose gonadotropins or different down-regulation methods proved to be fruitless. On the other hand, IVF using donated oocytes has very high pregnancy rates. It also allows for the genetic contribution of the patient’s partner and for the patient to experience pregnancy and childbirth. Women with POF should be counseled regarding availability of donor oocyte IVF. However, Turner syndrome is considered a contraindication to pregnancy. Gestational carrier receiving embryos formed with donor oocytes and partner’s sperm is an option for women with Turner syndrome. In summary, POF is a devastating diagnosis that has significant emotional and clinical long-term consequences. Timely diagnosis, counseling, and intervention may alleviate some of these consequences.

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21. 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(1):23–31. 22. Takebayashi K, Takakura K, Wang H, et al. Mutation analysis of the growth differentiation factor-9 and -9B genes in patients with premature ovarian failure and polycystic ovary syndrome. Fertil Steril 2000;74(5):976–9. 23. Karnis MF. Fertility, pregnancy, and medical management of Turner syndrome in the reproductive years. Fertil Steril 2012;98(4):787–91. 24. Atsma F, Bartelink ML, Grobbee DE, et al. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006;13(2):265–79. 25. Lokkegaard E, Jovanovic Z, Heitmann BL, et al. The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy. Maturitas 2006;53(2):226–33. 26. 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):3907–13. 27. Mondul AM, Rodriguez C, Jacobs EJ, et al. Age at natural menopause and cause-specific mortality. Am J Epidemiol 2005;162(11):1089–97. 28. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701–12. 29. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33. 30. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115(7): 840–5. 31. Renoux C, Dell’aniello S, Garbe E, et al. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ 2010;340: c2519. 32. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 2010;17(3):480–6. 33. Kangas L, Unkila M. Tissue selectivity of ospemifene: pharmacologic profile and clinical implications. Steroids 2013;78(12–13):1273–80. 34. Khan SN, Craig L, Wild R. Osteoporosis: therapeutic guidelines. Guidelines for practice management of osteoporosis. Clin Obstet Gynecol 2013;56(4): 694–702.

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Premature ovarian failure: clinical presentation and treatment.

Premature ovarian failure is a devastating diagnosis for reproductive-aged women. The diagnosis is relatively easy. However, it has serious health con...
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