J Endocrinol Invest DOI 10.1007/s40618-014-0231-1
SHORT REVIEW
Premature ovarian insufficiency: from pathogenesis to clinical management S. Luisi · C. Orlandini · C. Regini · A. Pizzo · F. Vellucci · F. Petraglia
Received: 28 November 2014 / Accepted: 16 December 2014 © Italian Society of Endocrinology (SIE) 2015
Abstract Premature ovarian insufficiency (POI) represents a condition characterized by the absence of normal ovarian function due to an incipient (by 3–10 years) ovarian aging. In most of the women affected there are no signs or symptoms that precede the interruption of menstruation and the onset of POI and the majority of women have a normal history of menarche, regular menstrual cycles and normal fertility. The possible genetic role in the development of POI has been largely demonstrated and many genes have been involved; on the other hand, ovary is not protected immunologically and the detection of autoantibodies directed against various ovarian targets strongly support the hypothesis of an autoimmune etiology. In approximately 5–10 % of women with a diagnosis of POI with a normal karyotype, a spontaneous pregnancy could occur even if the recovery of ovarian function is temporary and poorly predictable. Embryo donation and adoption are other alternatives that should be considered. POI and subsequent loss of reproductive capacity is a devastating condition and a difficult diagnosis for women to accept so it requires an individualized and a multidisciplinary approach. Hormonal replacement therapy (HRT) should be commenced as soon as possible to prevent and to contrast the onset of the symptoms related to hypoestrogenism and to improve the quality of life for these women.
S. Luisi (*) · C. Orlandini · C. Regini · A. Pizzo · F. Vellucci · F. Petraglia Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Policlinico “Le Scotte” Viale Bracci, 53100 Siena, Italy e-mail: [email protected]
Keywords Premature ovarian insufficiency · Genetic disorders · Ovarian reserve markers · Fertility preservation · Menopause
Introduction Premature ovarian insufficiency (POI) represents a condition characterized by the absence of normal ovarian function due to the depletion of the primordial follicle pool; ovarian follicles produce inhibin and estradiol, which in turn regulate the production of FSH [1]. According to the World Health Organization (WHO), abnormal ovarian function is classified into three different subgroups: disturbance at the hypothalamic-pituitary level causing a hypogonadotropic condition (WHO I); disturbance of the pituitary-ovarian balance, causing a normogonadotropic oligo- or amenorrheic state (WHO II); ovarian dysfunction causing a hypergonadotropic state due to follicle pool exhaustion (WHO III) [2]. The median age of menopause in Western women’s population is approximately 51 years. While very late (i.e., after 54 years) menopause is exceedingly uncommon, a sizeable minority of women experience cessation of ovarian function at or prior to age 45. By convention, menopause that occurs at ages 40–45 is considered “early” and characterized about 5 % of women. Biochemical and other hormonal analysis such as free thyroxin, TSH, prolactin and testosterone are recommended; a karyotype analysis, in particular in women less than 30 years of age, and an ultrasound scan of the breasts and the pelvis are advisable. POI is not merely an early menopause; up to 50 % of the patients with POI will have intermittent and unpredictable ovarian function which may persist for some years and it is
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characterized by low levels of gonadal hormones (estrogen and inhibins) and high levels of gonadotropins (in particular FSH). Initially, POI was thought to be permanent, but it is now believed that spontaneous remissions and even pregnancies are possible in affected women.
Etiology of POI Fig. 1 Causes of premature ovarian insufficiency
The exact etiology of POI is still unknown and in most cases, the etiology of POI remains elusive even if several rare specific causes have been identified. For most of the women the diagnosis of POI is unexpected, stressful and is accompanied by unpleasant physical symptoms that often coincide with the diagnosis of infertility. In the context of a normal female reproductive life, many environmental and lifestyle factors have been suggested to be related to POI: age of natural menopause, use of oral contraceptives, parity and smoking; however, these factors do not consistently explain the variation of the menopausal age. Most importantly, there is a strong association between ovarian aging and the number and quality of the remaining oocytes. Despite the presence of numerous studies of POI, the process of ovarian aging remains largely ignored. Subfertility generally becomes evident at 35–38 years old and at the age of 40 years, 90 % of the women are infertile. Although, during the first 5–7 years of menopause, ovaries continue to produce normal levels of androgens that could result in metabolic abnormalities, different atherogenic lipid profile, hair loss and also hirsutism; in case of POI, these natural processes occur earlier than expected [3]. Even if the etiology of POI remains unknown, the majority of causes are associated with either a genetic disorder, autoimmunity, iatrogenic or idiopathic causes (Fig. 1). Genetic disorders Some studies have reported the development of POI can be inherited suggesting a genetic mechanism may be involved in its onset [4]. Estimates of this heritability have been demonstrated, ranging from 30 to 85 %; in fact the onset of menopause before 45 years is fourfold–ninefold more frequent if one other family member such as the mother, sister, aunt, cousin or grandmother is affected by POI. Furthermore, the risk of POI is higher if mother or sister is affected or if there are simultaneously two related women affected in the same family [5]. A genetic assessment could be useful to identify genes and pathways involved in POI and if a genetic alteration is found it can be an important discussion for family counseling to plan for future reproductive activity. Defects involving aberration of X chromosome have been implicated in the diagnosis of POI [6]. The X
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chromosome rearrangements represent the major cause of primary amenorrhea associated with ovarian dysgenesis; this is because the two X chromosomes appear to be necessary for a complete ovarian function. The most frequent defect is represented by the Turner syndrome which is characterized by X chromosome monosomy (45, X) with an incidence of 1/2,500 females. Clinically, these women are characterized by primary amenorrhea (gonadal dysgenesis), sexual infantilism, webbing of the neck, cubitus valgus and short stature. With a high percentage of success, women affected by Turner syndrome could achieve pregnancy using donor oocytes. In these women, pregnancy could be compromised by a high percentage of aorta dissection/rupture and hypertension; for these reasons, they should be carefully evaluated before pregnancy [7]. Trisomy X (47,XXX) is a sex aneuploidy condition and occurs in approximately 1/1,000 females. Non-mosaic karyotypes are the most frequent, whereas mosaicism occurs approximately in 10 % of cases with different combinations (45,X/47,XXX, 45,X/46,XX/47,XXX) [8]. Both the short and the long arm of X chromosome seem to contain important genes implicated in ovarian function and deletions of the short arm of the X chromosome result in primary or secondary ovarian failure. Clinically these women are characterized by epicanthal folds, hypertelorism, overlapping digits, pes planus, pectus excavatum, and in some cases hypotonia may be present. Around 21 % of cases of familiar POI are associated with the pre-mutation of FMR1, located in the X chromosome; the consequence of the full mutation is the fragile X syndrome characterized by mental retardation. Sullivan et al. observed that this gene pre-mutation carrier has a frequency of 13 times higher POI, and in case of POI these women are 5 years younger compared with control women [9]. The FMR2 gene is located at Xq28 and the mechanisms generating diseases are similar to those of FMR1. BMP15 is a member of the large family of the TGFβ proteins involved in lots of processes during embryonic development and tissue formation. BMP15 is located in Xp11.2 and in the ovary it is expressed only in the oocytes during follicologenesis. It was demonstrated that an adequate posttranscriptional process of BMP15 represents a critical step
J Endocrinol Invest
in female fertility and oocyte quality. Mutations of BMP15 genes could predispose women to POI [10]. Considering that the initial follicular pool size and rate of follicular depletion are associated with the age of menopause, genetic variants in sex hormone receptor genes could affect the risk of POI [11]. Ovarian estradiol exerts either a negative or positive effect on the hypothalamic axis to regulate synthesis and secretion of pituitary gonadotropins: LH and FSH. Polymorphisms of ERα and ERβ genes are associated with altered hormonal profiles and reproductive patterns in terms of menarche and menopause. Many other genes and receptors have been involved in POI development such as LHr, FSHr, INHA, FOXL2, FOXO3, SF1, and CYP19A1 [12] (Table 1). Autoimmunity The ovary is not protected immunologically and the detection of autoantibodies directed against various ovarian targets supports the hypothesis of an autoimmune etiology may generate POI. The most common autoimmune diseases associated with POI are hypothyroidism, type I diabetes mellitus, hyperparathyroidism, Addison’s disease, myasthenia gravis, thymic hypoplasia/aplasia, Crohn’s disease, vitiligo, pernicious anemia, systemic lupus erytematosus, rheumatoid arthritis, type I and type II autoimmune polyglandular failure syndrome [13, 14]. In all these conditions, both premature follicular depletion and follicular dysfunction could be present. Iatrogenic causes of POI In 3 % of the cases the diagnosis of cancer is made in women under 40 years of age. The development of POI secondary to chemotherapy is strictly related to the therapy, Table 1 Different genes involved in POI Gene X-Linked BMP 15 FMR1 FMR2 Autosomal genes LHR FSHR INHA FOXL2 FOX03 ERα SF1 ERβ CYP19A1
Chromosomal localization
Xp11.2 Xq27.3 Xq28 2p21 2p21 2q33–q36 3q23 6q21 6q25 11q13 14q23.2 15q21.1
to the age at the start of the treatment and also to the combination of drugs used. It is estimated that the younger the patient, the higher the risk of ovarian damage. Similarly, the use of radiotherapy could cause follicular apoptosis and determine the reduction of the total pool of oocytes; obviously if the radiotherapy is not direct to pelvic target, the risk of POI is reduced [15]. Idiopathic causes of POI Other causes of POI could be related to infections, toxic chemicals, drugs, extensive surgery, enzyme deficiencies and metabolic disease. Lifestyle and habits (cigarette smoking, excessive consumption of alcohol and caffeine) are associated with a younger age at menopause, but not at the onset of POI [16, 17]. The exposure to “chemical endocrine disruptor” (EDC), an exogenous agent that interferes with the synthesis, release, transport and metabolism of an organism, has been described as a potent toxic agent for the ovary which could indirectly affect hormone levels interfering with the development of the ovarian follicles [18].
Ovarian reserve markers The term “ovarian reserve” is used to describe the potential functionality of ovaries and reflects the number and quality of oocytes and used for determining the state of reproductive aging. During the fourth month of fetal development, the ovaries contain about 6–7 million oocytes; these primordial follicles follow a process of apoptosis resulting, at the time of birth, a reduction in oocytes to 1–2 million. After birth, the percentage of follicles gradually decreases and, at the time of menarche, it declines to 300,000–400,000. By the time females reach reproductive age this decline stops, with a steady depletion of about 1,000 follicles per month, which then start to grow again after 37 years of age. With the onset of menopause, the number of follicles remaining is less than 1,000. In Western society, more women have delayed the time of their first pregnancy without considering that after the age of 35 there is a reduction in ovarian reserve. Numerous studies have shown that just measuring FSH is not sufficient to predict ovarian reserve and other markers, such as follicle count, inhibin B, anti- Mullerian hormone (AMH), should be evaluated [19] (Fig. 2). Follicle stimulating hormone (FSH) The rise of gonadotropins, in particular FSH, is essential for the diagnosis of menopause and POI and the predictive accuracy is supported by many reports in literature. To date, the limit value of FSH is 20 IU/l, below which the presence
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Fig. 2 Endocrine pathways and ovarian reserve in women with premature ovarian insufficiency
of a certain proportion of ovarian reserve is still possible; nevertheless, there is a low chance of pregnancy [20]. Antral Follicles Count (AFC) Ovarian reserve correlates with the number of antral follicles detected by ultrasound scan during the early follicular phase. The volume of both ovaries greater than 6 cm3 and the AFC greater than 7 represents an excellent indicator of ovarian reserve. Unfortunately, AFC provides information only on the number of follicles, not oocytes, and it does not provide information on their quality [21].
produced by granulosa cells of primary follicles starting from 32 weeks of gestation. It seems to have a role as a co-regulator in steroidogenesis and its levels appear to be related to those of estradiol [23]. During the menstrual cycle, an inter- and intra-cycle variability in serum AMH levels is present. When compared with other markers, AMH may better reflect the continuous decrease in the pool of oocytes and follicles during life and it could be used as a reliable and early marker of ovarian damage and as a predictor outcome in infertile women. In addition, a significant positive correlation between AMH levels, oocyte quality and embryo morphology has been demonstrated [24].
Inhibin B Inhibins belong to a family of growth factors and play a key role in regulating the hypothalamic-pituitary-ovarian axis acting on gonad maturation. During menopausal transition and in women with POI, blood levels of inhibin B are significantly reduced. However, blood levels of inhibin have a low capacity for differentiating women with an early onset POI when compared to controls, resulting in it being less predictive when compared to AMH [22]. Anti‑Mullerian hormone Anti-Mullerian hormone (AMH) is a dimeric glycoprotein that belongs to the super family of TGF-β and it is
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Symptoms of POI The diagnosis of POI results in the loss of ability to procreate and requires a significant level of psychological as well as medical support. Women experience a sense of inadequacy with this diagnosis which ultimately can affect their relationships. Both the emotional and psychological changes in these women may be exacerbated by a decrease in estrogens which causes central nervous system changes such as altered concentrations of neurotransmitters (norepinephrine, dopamine and serotonin), neuropeptides (opioids) and neurosteroid. Another important consideration is the impact of androgen deficiency
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associated with POI which may affect sexual activity, energy and mood. Women with a diagnosis of POI show menopausal signs and symptoms such as night sweats, hot flashes, tachycardia, vaginal dryness, dyspareunia, and recurrent urogenital infections, because of estrogen deficiency. Moreover psycho-affective symptoms such as emotional lability, irritability, and sleep disorders could be present. The pathogenetic mechanism behind this phenomenon is still unclear, although a central role is played by estrogenic deficiency that accelerates atherosclerosis and endothelial dysfunction and high levels of serum triglycerides that alter the lipid profile [25]. The relative increase of androgens causes perhaps a reduced insulin sensitivity because of the reduced LDL receptors activity due to estrogen deficiency [26].
Diagnosis of POI There is no consensus on criteria to identify POI in adolescents and young women and often diagnosis is delayed. In case of amenorrhea, a clinical evaluation comprehensive of gynecological and obstetrical history, details of previous uterine surgery, presence of symptoms of menopause, family history of early menopause, infertility or autoimmune disease should be investigated. The physical examination should focus on body form, evidence of normal secondary sexual characteristics and breast development. In young females, it is important to evaluate amenorrhea or a change from regular to irregular menses for three or more consecutive months in the absence of hormonal preparation such as oral contraceptives, for all potential causes including pregnancy, thyroid abnormalities, hyperprolactinemia, polycystic ovary syndrome, hypothalamic amenorrhea and premature ovarian insufficiency. If a diagnosis of POI is suspected, initial laboratory evaluation includes measurements of basal FSH and estradiol levels. If FSH levels are elevated into the menopausal range (FSH greater than 30–40 UI/l), a repeat FSH measurement is indicated within 1 month of the last blood test. If the result is confirmed, a diagnosis of POI can be established. Estradiol levels of less than 50 pg/ml indicate hypoestrogenism. Antimüllerian hormone and inhibin B should be evaluated [27]. Other diagnostic tests include transvaginal ultrasound scan of the ovaries: findings of a normal ovarian size/volume and the presence of a high antral ovarian follicle count make the diagnosis of POI less likely [28, 29]. Once a diagnosis of POI is established, further testing such as karyotyping, adrenal antibodies, FMR1 premutation and measurement of bone mineral density should be evaluated to investigate the possible etiology of POI [27].
Management of POI POI results in all the complications associated with the menopause but at a much younger age. The increased risk of osteoporosis and cardiovascular disease may be limited by an early diagnosis and treatment with HRT. Hormonal support involves daily therapy with the goal of maintenance of normal ovarian functioning levels of estradiol. Oral HRT administration is not recommended as first choice of treatment because of the higher hormone concentrations produced by HRT relative to the concentrations required by the patient [30]. Transdermal, oral or transvaginal estradiol in doses of 100 micrograms daily is the therapy of choice to mimic a physiologic dose range and to achieve symptoms relief. The addition of cyclic progesterone for 10–12 days each month is protective against endometrial hyperplasia and endometrial cancer [27]. Oral estradiol may be used, but it increases the risk of thromoembolism due to the firstpass effect on the liver; for this reason, transdermal HRT may be preferred in women with coagulation disturbances and those more prone to thrombosis, such as patients with thrombophilias [31]. Androgen replacement therapy is indicated for the treatment of early menopause to improve the sexuality of these women, muscular tropism and mood [32]. Androgens act on folliculogenesis and on inhibition of follicular atresia and, therefore, to restore normal levels of androgens may be useful to re-establish ovarian activity in women with POI. DHEA administration is important to increase the number of follicles recruited and to increase the chance of spontaneous ovulation and pregnancy. There is currently a lack of scientific evidence for the use of HRT in young women with POI because they need higher doses of estrogens than menopause women to ensure adequate replacement. In these patients, with absent or incomplete breast development, estrogen therapy should start with a low dose of HRT which could be increased slowly before administration of graduated progesterone dosages until a complete pubertal growth and sexual maturity. In some women, a higher incidence of spotting during HRT is possible due to the persistence of residual ovarian activity, even if a continuous hormone regimen is applied. HRT has no contraceptive properties and it should be taken until the age of 50 years which is the median age of physiological menopause. Appropriate HRT (cyclic or continuous) is useful to relieve symptoms of hypoestrogenism and to improve the quality of life of these women. Moreover, it is beneficial in preventing adverse consequences such as the risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis and ischemic heart disease. Hormonal treatment will be integrated with a healthy lifestyle (abstaining from cigarette smoking, balanced diet). The “North American Menopause Society” recommends the intake of 1,200 mg calcium per
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day, 800–100 IU of vitamin D and a regular physical activity (walking, running, resistance exercises) [33]. Women diagnosed with POI should undergo annual visits to assess general health status and the effectiveness of the adopted treatment; bone densitometry should be performed at least once every 2–3 years to monitor the mineralization of the skeleton.
Fertility preservation and reproduction in women with POI Fertility may persist even when few functional follicles are present. Despite a diagnosis of POI, there is a 5–10 % chance of spontaneous pregnancy [34]. Unless pregnancy is desired, a discussion of effective contraception should be taken; although oral contraceptives are commonly prescribed, the use of barrier methods or intrauterine device should be encouraged, because the effectiveness of oral contraceptives has not been studied in women with POI, and there are some reports of women who have conceived perhaps because of a failure of the oral contraceptive to suppress the high FSH levels that are characteristic of this condition. If a patient chooses a non estrogen method of contraception, estrogen should be administrated to preserve bone mineral density and prevent other adverse effects of hypoestrogenemia [27]. Counseling regarding future childbearing options will be necessary prior to initiation of chemotherapy or radiation treatment; options for fertility preservation including ovarian hyperstimulation with oocyte retrieval followed by oocyte or embryo cryopreservation, ovarian tissue cryopreservation, or ovarian suppression with a gonadotropin-releasing hormone agonist will be necessary [1, 35]. Embryo donation and adoption are other alternatives that should be discussed with the women [36].
Conclusion Women with a diagnosis of POI experience a range of psychological and physiological effects which can reduce their procreative capacity and their desire to be pregnant. The medical approach for these women should involve not only the gynecologist but also a geneticist, an endocrinologist, a psychologist and a dietician for adequate nutritional advice. Appropriate HRT is useful for relief of symptoms of hypoestrogenism and to improve the quality of life for these women. Conflict of interest None.
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References 1. Cox L, Liu JH (2014) Primary ovarian insufficiency: an update. Int J Womens Health 20(6):235–243 2. ESHRE Capri Workshop Group (2005) Noncontraceptive health benefits of combined oral contraception. Hum Reprod Update 11:513–525 3. Broekmans FJ, Soules MR, Fauser BC (2009) Ovarian aging: mechanisms and clinical consequences. Endocr Rev 30:465–493 4. Van Asselt KM, Kok HS, Pearson PL et al (2004) Heritability of menopausal age in mothers and daughters. Fertil Steril 82:1348–1351 5. Janse F, Knauff EA, Niermeijer MF et al (2010) Dutch Premature Ovarian Failure Consortium. Similar phenotype characteristics comparing familial and sporadic premature ovarian failure. Menopause 17:758–765 6. Cordts BC, Christofolini DM, Dos Santos AA, Bianco B, Barbosa CP (2011) Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet 283:635–643 7. Karnis MF (2012) Fertility, pregnancy, and medical management of Turner syndrome in the reproductive years. Fertil Steril 98:787–791 8. Bidet M (2011) Resumption of Ovarian Function and Pregnancies in 358 Patients with Premature Ovarian Failure. J Clin Endocrinol Metab 96:3864–3872 9. Sullivan AK, Marcus M, Epstein MP et al (2005) Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 20:402–412 10. Otsuka F, McTavish KJ, Shimasaki S (2011) Integral role of GDF-9 and BMP-15 in ovarian function. Mol Reprod Dev 78:9–21 11. Yoon SH, Choi YM, Hong MA et al (2010) Estrogen receptor alpha gene polymorphisms in patients with idiopathic premature ovarian failure. Hum Reprod 25:283–287 12. Rafique S, Sterling E, Lawrence N (2012) A new approach to primary ovarian insufficiency. Obstet Gynecol Clin N Am 39:567–586 13. Hoek A, Schoemaker J, Drexhage HA (1997) Premature ovarian failure and ovarian autoimmunity. Endocr Rev 18:107–134 14. La Marca A, Marzotti S, Brozzetti A et al (2009) Italian Addison Network. Primary ovarian insufficiency due to steroidogenic cell autoimmunity is associated with a preserved pool of functioning follicles. J Clin Endocrinol Metab 94:3816–3823 15. Bedoschi G, Turan V, Oktay K (2013) Utility of GnRH-agonists for fertility preservation in women with operable breast cancer: is it protective? Curr Breast Cancer Rep 5:302–308 16. Trikudanathan S, Pedley A, Massaro JM et al (2013) Association of female reproductive factors with body composition: the Framingham Heart Study. J Clin Endocrinol Metab 98:236–244 17. Kinney A, Kline J, Kelly A, Reuss ML, Levin B (2007) Smoking, alcohol and caffeine in relation to ovarian age during the reproductive years. Hum Reprod 22:1175–1185 18. Iorio R, Castellucci A, Ventriglia G et al (2014) Ovarian toxicity: from environmental exposure to chemotherapy. Curr Pharm Des 20:5388–5397 19. Knauff EAH, Eijkemans MJC, Lambalk CB et al (2009) AntiMu˝llerian hormone, inhibin B, and antral follicle count in young women with ovarian failure. J Clin Endocrinol Metab 94:786–792 20. Van der Steeg JW, Steures P, Eijkemans MJ et al (2007) Predictive value and clinical impact of basal follicle-stimulating hormone in subfertile, ovulatory women. J Clin Endocrinol Metab 92:2163–2168 21. Van Disseldorp J, Lambalk CB, Kwee J et al (2010) Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts. Hum Reprod 25:221–227
J Endocrinol Invest 22. Luisi S, Ciani V, Podfigurna-Stopa A et al (2012) Serum antiMüllerian hormone, inhibin B, and total inhibin levels in women with hypothalamic amenorrhea and anorexia nervosa. Gynecol Endocrinol 28:34–38 23. Andersen CY, Byskov AG (2006) Estradiol and regulation of anti-Müllerian hormone, inhibin-A, and inhibin-B secretion: analysis of small antral and preovulatory human follicles’ fluid. J Clin Endocrinol Metab 91:4064–4069 24. Silberstein T, MacLaughlin DT, Shai I et al (2006) Mullerian inhibiting substance levels at the time of HCG administration in IVF cycles predict both ovarian reserve and embryo morphology. Hum Reprod 21:159–163 25. Kalantaridou SN, Naka KK, Bechlioulis A, Makrigiannakis A, Michalis L, Chrousos GP (2006) Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement. Trends Endocrinol Metab 17:101–109 26. Rocca WA, Bower JH, Maraganore DM et al (2008) Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 70:200–209 27. Primary ovarian insufficiency in adolescent and young women. Committee Opinion. No 605. ACOG. Obstet and Gynecol 2014, 123: 193-7 28. Rebar RW (2009) Premature ovarian failure. Obstet Gynecol 113:1355–1363 29. Parker WH, Broder MS, Chang E et al (2009) Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet Gynecol 113:1027–1037
30. Nelson LM (2009) Clinical practice. Primary ovarian insuffi ciency. N Engl J Med 360:606–614 31. Scarabin PY, Oger E, Plu-Bureau G (2003) Estrogen and ThromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362:428–432 32. Bachmann G, Bancroft J, Braunstein G et al (2002) Princeton. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 77:660–665 33. Martyn-St James M, Carroll S (2008) Meta-analysis of walking for preservation of bone mineral density in postmenopausal women. Bone 43:521–531 34. De Caro JJ, Dominguez C, Sherman SL (2008) Reproduc tive 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. 1135:99–111 35. Lucas K, Hensel D (2014) Fertility preservation options for women treated for cancer. Nurs Womens Health 18:138–147 36. Krieg SA, Henne MB, Westphal LM (2008) Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil Steril 90:65–70
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SHORT REVIEW
Premature ovarian insufficiency: from pathogenesis to clinical management S. Luisi · C. Orlandini · C. Regini · A. Pizzo · F. Vellucci · F. Petraglia
Received: 28 November 2014 / Accepted: 16 December 2014 © Italian Society of Endocrinology (SIE) 2015
Abstract Premature ovarian insufficiency (POI) represents a condition characterized by the absence of normal ovarian function due to an incipient (by 3–10 years) ovarian aging. In most of the women affected there are no signs or symptoms that precede the interruption of menstruation and the onset of POI and the majority of women have a normal history of menarche, regular menstrual cycles and normal fertility. The possible genetic role in the development of POI has been largely demonstrated and many genes have been involved; on the other hand, ovary is not protected immunologically and the detection of autoantibodies directed against various ovarian targets strongly support the hypothesis of an autoimmune etiology. In approximately 5–10 % of women with a diagnosis of POI with a normal karyotype, a spontaneous pregnancy could occur even if the recovery of ovarian function is temporary and poorly predictable. Embryo donation and adoption are other alternatives that should be considered. POI and subsequent loss of reproductive capacity is a devastating condition and a difficult diagnosis for women to accept so it requires an individualized and a multidisciplinary approach. Hormonal replacement therapy (HRT) should be commenced as soon as possible to prevent and to contrast the onset of the symptoms related to hypoestrogenism and to improve the quality of life for these women.
S. Luisi (*) · C. Orlandini · C. Regini · A. Pizzo · F. Vellucci · F. Petraglia Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Policlinico “Le Scotte” Viale Bracci, 53100 Siena, Italy e-mail: [email protected]
Keywords Premature ovarian insufficiency · Genetic disorders · Ovarian reserve markers · Fertility preservation · Menopause
Introduction Premature ovarian insufficiency (POI) represents a condition characterized by the absence of normal ovarian function due to the depletion of the primordial follicle pool; ovarian follicles produce inhibin and estradiol, which in turn regulate the production of FSH [1]. According to the World Health Organization (WHO), abnormal ovarian function is classified into three different subgroups: disturbance at the hypothalamic-pituitary level causing a hypogonadotropic condition (WHO I); disturbance of the pituitary-ovarian balance, causing a normogonadotropic oligo- or amenorrheic state (WHO II); ovarian dysfunction causing a hypergonadotropic state due to follicle pool exhaustion (WHO III) [2]. The median age of menopause in Western women’s population is approximately 51 years. While very late (i.e., after 54 years) menopause is exceedingly uncommon, a sizeable minority of women experience cessation of ovarian function at or prior to age 45. By convention, menopause that occurs at ages 40–45 is considered “early” and characterized about 5 % of women. Biochemical and other hormonal analysis such as free thyroxin, TSH, prolactin and testosterone are recommended; a karyotype analysis, in particular in women less than 30 years of age, and an ultrasound scan of the breasts and the pelvis are advisable. POI is not merely an early menopause; up to 50 % of the patients with POI will have intermittent and unpredictable ovarian function which may persist for some years and it is
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characterized by low levels of gonadal hormones (estrogen and inhibins) and high levels of gonadotropins (in particular FSH). Initially, POI was thought to be permanent, but it is now believed that spontaneous remissions and even pregnancies are possible in affected women.
Etiology of POI Fig. 1 Causes of premature ovarian insufficiency
The exact etiology of POI is still unknown and in most cases, the etiology of POI remains elusive even if several rare specific causes have been identified. For most of the women the diagnosis of POI is unexpected, stressful and is accompanied by unpleasant physical symptoms that often coincide with the diagnosis of infertility. In the context of a normal female reproductive life, many environmental and lifestyle factors have been suggested to be related to POI: age of natural menopause, use of oral contraceptives, parity and smoking; however, these factors do not consistently explain the variation of the menopausal age. Most importantly, there is a strong association between ovarian aging and the number and quality of the remaining oocytes. Despite the presence of numerous studies of POI, the process of ovarian aging remains largely ignored. Subfertility generally becomes evident at 35–38 years old and at the age of 40 years, 90 % of the women are infertile. Although, during the first 5–7 years of menopause, ovaries continue to produce normal levels of androgens that could result in metabolic abnormalities, different atherogenic lipid profile, hair loss and also hirsutism; in case of POI, these natural processes occur earlier than expected [3]. Even if the etiology of POI remains unknown, the majority of causes are associated with either a genetic disorder, autoimmunity, iatrogenic or idiopathic causes (Fig. 1). Genetic disorders Some studies have reported the development of POI can be inherited suggesting a genetic mechanism may be involved in its onset [4]. Estimates of this heritability have been demonstrated, ranging from 30 to 85 %; in fact the onset of menopause before 45 years is fourfold–ninefold more frequent if one other family member such as the mother, sister, aunt, cousin or grandmother is affected by POI. Furthermore, the risk of POI is higher if mother or sister is affected or if there are simultaneously two related women affected in the same family [5]. A genetic assessment could be useful to identify genes and pathways involved in POI and if a genetic alteration is found it can be an important discussion for family counseling to plan for future reproductive activity. Defects involving aberration of X chromosome have been implicated in the diagnosis of POI [6]. The X
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chromosome rearrangements represent the major cause of primary amenorrhea associated with ovarian dysgenesis; this is because the two X chromosomes appear to be necessary for a complete ovarian function. The most frequent defect is represented by the Turner syndrome which is characterized by X chromosome monosomy (45, X) with an incidence of 1/2,500 females. Clinically, these women are characterized by primary amenorrhea (gonadal dysgenesis), sexual infantilism, webbing of the neck, cubitus valgus and short stature. With a high percentage of success, women affected by Turner syndrome could achieve pregnancy using donor oocytes. In these women, pregnancy could be compromised by a high percentage of aorta dissection/rupture and hypertension; for these reasons, they should be carefully evaluated before pregnancy [7]. Trisomy X (47,XXX) is a sex aneuploidy condition and occurs in approximately 1/1,000 females. Non-mosaic karyotypes are the most frequent, whereas mosaicism occurs approximately in 10 % of cases with different combinations (45,X/47,XXX, 45,X/46,XX/47,XXX) [8]. Both the short and the long arm of X chromosome seem to contain important genes implicated in ovarian function and deletions of the short arm of the X chromosome result in primary or secondary ovarian failure. Clinically these women are characterized by epicanthal folds, hypertelorism, overlapping digits, pes planus, pectus excavatum, and in some cases hypotonia may be present. Around 21 % of cases of familiar POI are associated with the pre-mutation of FMR1, located in the X chromosome; the consequence of the full mutation is the fragile X syndrome characterized by mental retardation. Sullivan et al. observed that this gene pre-mutation carrier has a frequency of 13 times higher POI, and in case of POI these women are 5 years younger compared with control women [9]. The FMR2 gene is located at Xq28 and the mechanisms generating diseases are similar to those of FMR1. BMP15 is a member of the large family of the TGFβ proteins involved in lots of processes during embryonic development and tissue formation. BMP15 is located in Xp11.2 and in the ovary it is expressed only in the oocytes during follicologenesis. It was demonstrated that an adequate posttranscriptional process of BMP15 represents a critical step
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in female fertility and oocyte quality. Mutations of BMP15 genes could predispose women to POI [10]. Considering that the initial follicular pool size and rate of follicular depletion are associated with the age of menopause, genetic variants in sex hormone receptor genes could affect the risk of POI [11]. Ovarian estradiol exerts either a negative or positive effect on the hypothalamic axis to regulate synthesis and secretion of pituitary gonadotropins: LH and FSH. Polymorphisms of ERα and ERβ genes are associated with altered hormonal profiles and reproductive patterns in terms of menarche and menopause. Many other genes and receptors have been involved in POI development such as LHr, FSHr, INHA, FOXL2, FOXO3, SF1, and CYP19A1 [12] (Table 1). Autoimmunity The ovary is not protected immunologically and the detection of autoantibodies directed against various ovarian targets supports the hypothesis of an autoimmune etiology may generate POI. The most common autoimmune diseases associated with POI are hypothyroidism, type I diabetes mellitus, hyperparathyroidism, Addison’s disease, myasthenia gravis, thymic hypoplasia/aplasia, Crohn’s disease, vitiligo, pernicious anemia, systemic lupus erytematosus, rheumatoid arthritis, type I and type II autoimmune polyglandular failure syndrome [13, 14]. In all these conditions, both premature follicular depletion and follicular dysfunction could be present. Iatrogenic causes of POI In 3 % of the cases the diagnosis of cancer is made in women under 40 years of age. The development of POI secondary to chemotherapy is strictly related to the therapy, Table 1 Different genes involved in POI Gene X-Linked BMP 15 FMR1 FMR2 Autosomal genes LHR FSHR INHA FOXL2 FOX03 ERα SF1 ERβ CYP19A1
Chromosomal localization
Xp11.2 Xq27.3 Xq28 2p21 2p21 2q33–q36 3q23 6q21 6q25 11q13 14q23.2 15q21.1
to the age at the start of the treatment and also to the combination of drugs used. It is estimated that the younger the patient, the higher the risk of ovarian damage. Similarly, the use of radiotherapy could cause follicular apoptosis and determine the reduction of the total pool of oocytes; obviously if the radiotherapy is not direct to pelvic target, the risk of POI is reduced [15]. Idiopathic causes of POI Other causes of POI could be related to infections, toxic chemicals, drugs, extensive surgery, enzyme deficiencies and metabolic disease. Lifestyle and habits (cigarette smoking, excessive consumption of alcohol and caffeine) are associated with a younger age at menopause, but not at the onset of POI [16, 17]. The exposure to “chemical endocrine disruptor” (EDC), an exogenous agent that interferes with the synthesis, release, transport and metabolism of an organism, has been described as a potent toxic agent for the ovary which could indirectly affect hormone levels interfering with the development of the ovarian follicles [18].
Ovarian reserve markers The term “ovarian reserve” is used to describe the potential functionality of ovaries and reflects the number and quality of oocytes and used for determining the state of reproductive aging. During the fourth month of fetal development, the ovaries contain about 6–7 million oocytes; these primordial follicles follow a process of apoptosis resulting, at the time of birth, a reduction in oocytes to 1–2 million. After birth, the percentage of follicles gradually decreases and, at the time of menarche, it declines to 300,000–400,000. By the time females reach reproductive age this decline stops, with a steady depletion of about 1,000 follicles per month, which then start to grow again after 37 years of age. With the onset of menopause, the number of follicles remaining is less than 1,000. In Western society, more women have delayed the time of their first pregnancy without considering that after the age of 35 there is a reduction in ovarian reserve. Numerous studies have shown that just measuring FSH is not sufficient to predict ovarian reserve and other markers, such as follicle count, inhibin B, anti- Mullerian hormone (AMH), should be evaluated [19] (Fig. 2). Follicle stimulating hormone (FSH) The rise of gonadotropins, in particular FSH, is essential for the diagnosis of menopause and POI and the predictive accuracy is supported by many reports in literature. To date, the limit value of FSH is 20 IU/l, below which the presence
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Fig. 2 Endocrine pathways and ovarian reserve in women with premature ovarian insufficiency
of a certain proportion of ovarian reserve is still possible; nevertheless, there is a low chance of pregnancy [20]. Antral Follicles Count (AFC) Ovarian reserve correlates with the number of antral follicles detected by ultrasound scan during the early follicular phase. The volume of both ovaries greater than 6 cm3 and the AFC greater than 7 represents an excellent indicator of ovarian reserve. Unfortunately, AFC provides information only on the number of follicles, not oocytes, and it does not provide information on their quality [21].
produced by granulosa cells of primary follicles starting from 32 weeks of gestation. It seems to have a role as a co-regulator in steroidogenesis and its levels appear to be related to those of estradiol [23]. During the menstrual cycle, an inter- and intra-cycle variability in serum AMH levels is present. When compared with other markers, AMH may better reflect the continuous decrease in the pool of oocytes and follicles during life and it could be used as a reliable and early marker of ovarian damage and as a predictor outcome in infertile women. In addition, a significant positive correlation between AMH levels, oocyte quality and embryo morphology has been demonstrated [24].
Inhibin B Inhibins belong to a family of growth factors and play a key role in regulating the hypothalamic-pituitary-ovarian axis acting on gonad maturation. During menopausal transition and in women with POI, blood levels of inhibin B are significantly reduced. However, blood levels of inhibin have a low capacity for differentiating women with an early onset POI when compared to controls, resulting in it being less predictive when compared to AMH [22]. Anti‑Mullerian hormone Anti-Mullerian hormone (AMH) is a dimeric glycoprotein that belongs to the super family of TGF-β and it is
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Symptoms of POI The diagnosis of POI results in the loss of ability to procreate and requires a significant level of psychological as well as medical support. Women experience a sense of inadequacy with this diagnosis which ultimately can affect their relationships. Both the emotional and psychological changes in these women may be exacerbated by a decrease in estrogens which causes central nervous system changes such as altered concentrations of neurotransmitters (norepinephrine, dopamine and serotonin), neuropeptides (opioids) and neurosteroid. Another important consideration is the impact of androgen deficiency
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associated with POI which may affect sexual activity, energy and mood. Women with a diagnosis of POI show menopausal signs and symptoms such as night sweats, hot flashes, tachycardia, vaginal dryness, dyspareunia, and recurrent urogenital infections, because of estrogen deficiency. Moreover psycho-affective symptoms such as emotional lability, irritability, and sleep disorders could be present. The pathogenetic mechanism behind this phenomenon is still unclear, although a central role is played by estrogenic deficiency that accelerates atherosclerosis and endothelial dysfunction and high levels of serum triglycerides that alter the lipid profile [25]. The relative increase of androgens causes perhaps a reduced insulin sensitivity because of the reduced LDL receptors activity due to estrogen deficiency [26].
Diagnosis of POI There is no consensus on criteria to identify POI in adolescents and young women and often diagnosis is delayed. In case of amenorrhea, a clinical evaluation comprehensive of gynecological and obstetrical history, details of previous uterine surgery, presence of symptoms of menopause, family history of early menopause, infertility or autoimmune disease should be investigated. The physical examination should focus on body form, evidence of normal secondary sexual characteristics and breast development. In young females, it is important to evaluate amenorrhea or a change from regular to irregular menses for three or more consecutive months in the absence of hormonal preparation such as oral contraceptives, for all potential causes including pregnancy, thyroid abnormalities, hyperprolactinemia, polycystic ovary syndrome, hypothalamic amenorrhea and premature ovarian insufficiency. If a diagnosis of POI is suspected, initial laboratory evaluation includes measurements of basal FSH and estradiol levels. If FSH levels are elevated into the menopausal range (FSH greater than 30–40 UI/l), a repeat FSH measurement is indicated within 1 month of the last blood test. If the result is confirmed, a diagnosis of POI can be established. Estradiol levels of less than 50 pg/ml indicate hypoestrogenism. Antimüllerian hormone and inhibin B should be evaluated [27]. Other diagnostic tests include transvaginal ultrasound scan of the ovaries: findings of a normal ovarian size/volume and the presence of a high antral ovarian follicle count make the diagnosis of POI less likely [28, 29]. Once a diagnosis of POI is established, further testing such as karyotyping, adrenal antibodies, FMR1 premutation and measurement of bone mineral density should be evaluated to investigate the possible etiology of POI [27].
Management of POI POI results in all the complications associated with the menopause but at a much younger age. The increased risk of osteoporosis and cardiovascular disease may be limited by an early diagnosis and treatment with HRT. Hormonal support involves daily therapy with the goal of maintenance of normal ovarian functioning levels of estradiol. Oral HRT administration is not recommended as first choice of treatment because of the higher hormone concentrations produced by HRT relative to the concentrations required by the patient [30]. Transdermal, oral or transvaginal estradiol in doses of 100 micrograms daily is the therapy of choice to mimic a physiologic dose range and to achieve symptoms relief. The addition of cyclic progesterone for 10–12 days each month is protective against endometrial hyperplasia and endometrial cancer [27]. Oral estradiol may be used, but it increases the risk of thromoembolism due to the firstpass effect on the liver; for this reason, transdermal HRT may be preferred in women with coagulation disturbances and those more prone to thrombosis, such as patients with thrombophilias [31]. Androgen replacement therapy is indicated for the treatment of early menopause to improve the sexuality of these women, muscular tropism and mood [32]. Androgens act on folliculogenesis and on inhibition of follicular atresia and, therefore, to restore normal levels of androgens may be useful to re-establish ovarian activity in women with POI. DHEA administration is important to increase the number of follicles recruited and to increase the chance of spontaneous ovulation and pregnancy. There is currently a lack of scientific evidence for the use of HRT in young women with POI because they need higher doses of estrogens than menopause women to ensure adequate replacement. In these patients, with absent or incomplete breast development, estrogen therapy should start with a low dose of HRT which could be increased slowly before administration of graduated progesterone dosages until a complete pubertal growth and sexual maturity. In some women, a higher incidence of spotting during HRT is possible due to the persistence of residual ovarian activity, even if a continuous hormone regimen is applied. HRT has no contraceptive properties and it should be taken until the age of 50 years which is the median age of physiological menopause. Appropriate HRT (cyclic or continuous) is useful to relieve symptoms of hypoestrogenism and to improve the quality of life of these women. Moreover, it is beneficial in preventing adverse consequences such as the risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis and ischemic heart disease. Hormonal treatment will be integrated with a healthy lifestyle (abstaining from cigarette smoking, balanced diet). The “North American Menopause Society” recommends the intake of 1,200 mg calcium per
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day, 800–100 IU of vitamin D and a regular physical activity (walking, running, resistance exercises) [33]. Women diagnosed with POI should undergo annual visits to assess general health status and the effectiveness of the adopted treatment; bone densitometry should be performed at least once every 2–3 years to monitor the mineralization of the skeleton.
Fertility preservation and reproduction in women with POI Fertility may persist even when few functional follicles are present. Despite a diagnosis of POI, there is a 5–10 % chance of spontaneous pregnancy [34]. Unless pregnancy is desired, a discussion of effective contraception should be taken; although oral contraceptives are commonly prescribed, the use of barrier methods or intrauterine device should be encouraged, because the effectiveness of oral contraceptives has not been studied in women with POI, and there are some reports of women who have conceived perhaps because of a failure of the oral contraceptive to suppress the high FSH levels that are characteristic of this condition. If a patient chooses a non estrogen method of contraception, estrogen should be administrated to preserve bone mineral density and prevent other adverse effects of hypoestrogenemia [27]. Counseling regarding future childbearing options will be necessary prior to initiation of chemotherapy or radiation treatment; options for fertility preservation including ovarian hyperstimulation with oocyte retrieval followed by oocyte or embryo cryopreservation, ovarian tissue cryopreservation, or ovarian suppression with a gonadotropin-releasing hormone agonist will be necessary [1, 35]. Embryo donation and adoption are other alternatives that should be discussed with the women [36].
Conclusion Women with a diagnosis of POI experience a range of psychological and physiological effects which can reduce their procreative capacity and their desire to be pregnant. The medical approach for these women should involve not only the gynecologist but also a geneticist, an endocrinologist, a psychologist and a dietician for adequate nutritional advice. Appropriate HRT is useful for relief of symptoms of hypoestrogenism and to improve the quality of life for these women. Conflict of interest None.
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