Chapter 20 Premature Ovarian Failure

INTRODUCTION

Premature ovarian failure is defined as hypergonadotropic hypogonadism before age 40. Premature ovarian failure is commonly but not uniformly associated with depletion of ovarian follicles, as is seen in menopause. It results in cessation of regular menses. This condition affects approximately 1% of all women, with 90% of cases occurring between ages 30 and 40. Premature ovarian failure will be found in 10% to 28% of women presenting with primary amenorrhea and 4% to 18% of women presenting with secondary amenorrhea.¹

In some cases, the etiology is identical to menopause and thus represents the occurrence of a normal physiologic process at an unusually young age. However, in many cases, the underlying cause is an identifiable pathology.

The goal of the clinician is to diagnose and, if possible, treat any ongoing pathologic conditions. Equally important is to help the affected woman reach any unfulfilled reproductive goals via assisted reproductive technologies and psychologically adjust to her condition. Finally, the clinician must ensure that the patient does not suffer the adverse sequelae of prolonged estrogen deprivation, most notably genital atrophy and osteoporosis.

This chapter describes normal ovarian development and gradual loss of function. Premature ovarian failure is described, including the various known causes and its standard evaluation. Finally, long-term management is covered.

OVARIAN EMBRYOLOGY

The primordial germ cells are known to originate from the endoderm of the yolk sac. These cells can be identified histologically as early as the end of the third week of gestation and migrate to the genital ridge.² By 8 weeks of intrauterine life, persistent mitosis increases the total number of oogonia to 600,000.³ From this point on, the oogonial endowment is subject to three simultaneous ongoing processes: mitosis, meiosis, and oogonial atresia. At approximately 20 weeks’ gestation, the ovaries possess the maximal complement of up to 6 million to 8 million primary oocytes, approximately two thirds of which have entered and arrested in the prophase of the first meiotic division.¹

From midgestation onward, relentless and irreversible attrition progressively diminishes the germ cell endowment of the gonad.⁴ Some of the oogonia depart from the mitotic cycle to enter the prophase of the first meiotic division between weeks 8 and 13 of fetal life. This change marks the conversion of these cells to primary oocytes well before actual follicle formation.

A role for steroids has been suggested in the control of ovarian primordial follicle assembly and early follicular development.⁵ It is generally presumed that usually no oogonia are present at birth. Unconfirmed data from mice has challenged this concept, however.⁶ These investigators have challenged the dogma that germline stem cells are not present and follicular renewal does not occur in the postnatal mammalian ovary.

Only 1 million germ cells are present at birth.⁷ This decreases further to approximately 300,000 by the onset of puberty. Of these follicles, only 400 to 500 (i.e., less than 1% of the total) ovulate in the course of a reproductive lifespan.⁸

Once formed, the primary oocyte persists in prophase of the first meiotic division until the time of ovulation, when meiosis is resumed and the first polar body is formed and extruded. It is generally presumed that a granulosa cell-derived putative meiosis inhibitor is in play. This hypothesis is based on the observation that denuded (granulosa-free) oocytes are capable of spontaneously completing meiotic maturation in vitro. The primary oocyte is converted into a secondary oocyte by completion of the first meiotic metaphase and formation of the first polar body, before actual ovulation but after the luteinizing hormone (LH) surge. At ovulation, the secondary oocyte and the surrounding granulosa cells (cumulus oophorus) are extruded.

NORMAL OVARIAN AGING

Ovarian aging, ultimately leading to ovarian failure and menopause, is a continuum. An early sign is a poor response to ovarian stimulation, followed by menstrual irregularities and eventually ending in cessation of ovarian follicle function. The time interval between the loss of menstrual regularity and the menopause is approximately 6 years, regardless of age at menopause.⁹ Consistent with this is the finding that the age of last delivery for Canadian women in the nineteenth century showed the same variation as the age of menopause but occurred 10 years earlier.¹⁰

Loss of Fertility and Ovarian Aging

Natural fertility is known to decline with maternal age. Normal women experience their peak fertility in their early 20s, and an accelerated decline is observed after age 35, as recorded in natural populations around the world.¹¹ The risk of clinical miscarriage and fetal aneuploidy both increase with maternal age, with a steep rise in the late 30s.^12,¹³ The cause of age-related deterioration of oocyte quality is generally accepted to be meiotic nondisjunction due to accumulation of damage in DNA and the microtubules of the meiotic spindle.¹⁰

Elevation of early follicular phase follicle-stimulating hormone (FSH) is a hallmark of diminishing ovarian follicular reserve, heralding the menopause transition.¹⁴ Elevated FSH levels noted in the premenopause are believed to cause a more rapid recruitment of the cohort of preantral follicles.¹⁵ Thus, a period of accelerated oocyte depletion begins until near-complete exhaustion of the follicles.¹⁶

Poor response to ovarian stimulation most likely represents women in a stage between onset of accelerated decline and total loss of fertility, whereas nonresponse corresponds to a total loss of fertility.¹⁷ The basis of the link between a poor response and an early menopause lies in the physiology of follicular development and depletion in the ovary. It has been suggested that the size of the antral follicle cohort is a reflection of the actual resting follicle pool.¹⁸^–²¹ “Poor responders” also become menopausal earlier.^22,²³

Menopause

The clinical sequelae of physiologic ovarian failure is menopause, which is defined as the permanent cessation of menses. The median age of menopause in the United States is 51 years, with menopause occurring before age 40 for 1% of women and beyond age 60 for another 1%.²⁴ Despite a progressive prolongation in the mean age of the population and a trend toward accelerated menarche, the age of menopause has remained relatively unaffected over the last century.²⁵ Evidence suggests that the time of the natural menopause is under strong genetic control, although environmental factors can play a significant role.²⁶

PATHOPHYSIOLOGY OF PREMATURE OVARIAN FAILURE

Premature ovarian failure is the absence of ovarian function before age 40. Although it can be the result of a physiologic process at an unusually young age, it is often due to a broad range of underlying etiologies. Regardless of etiology, the clinical results are decreased fertility, and hypoestrogenemia ultimately manifesting as amenorrhea.

In most cases, the etiology of premature ovarian failure will not be clear, and the majority of cases occur sporadically. However, there is a genetic component in some woman, and the risk of premature ovarian failure in a woman with a first-degree relative with premature ovarian failure is between 4% and 30%.^27,²⁸ Multiple known etiologies of premature ovarian failure are presented here (Table 20-1).

Table 20-1 Causes of Premature Ovarian Failure

Genetic Causes

Genetic errors such as single-gene defects, abnormalities in the sex chromosomes, and other poorly defined genetic diseases have been associated with premature ovarian failure. The list of potential disorders associated with premature ovarian failure is extensive; however, some general patterns have been observed.

Single-Gene Defects

Single-gene defects may give rise to ovarian failure. These include mutations of FSH and LH receptors, inhibin, and galactosemia, among others.^29,³⁰

Gonadotropin Receptor Polymorphism

A mutation of the FSH receptor has been described in a subset of patients with premature ovarian failure.³¹ This is associated with loss in receptor function and appears confined to specific families in the Finnish population. A defect in the LH receptor gene associated with ovarian resistance has also been described.³²

Inhibin Polymorphism

Mutations in the inhibin α and β genes have been associated with relatively severe symptoms of premature ovarian failure. Amenorrhea usually develops by the second decade of life in 7% of patients exhibiting this mutation, compared to 0.7% of controls.³³

Galactosemia

In females affected with this autosomal recessive disorder, the incidence of premature ovarian failure is at least 80%.³⁴ A relevant murine model suggests that this might be due to a decrease in the germ cell number during fetal oogenesis.³⁵ Mutations of the galactose-1-phosphate uridyltransferase gene can also result in premature ovarian failure because of ovarian accumulation of galactose metabolites at toxic levels.³⁶ Other possible mechanisms contributing to premature ovarian failure in these patients include defective isoforms of FSH, and follicular dysfunction that may be related to interference with nucleotide sugar metabolism and the synthesis of galactose-containing glycoproteins and glycolipids consequent to the enzymatic defect.^1,³⁷

Other Genetic Abnormalities

Several autosomal loci have been implicated in premature ovarian failure.³⁸ For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, whereby lesions result in decreased follicles. Deficiencies of 17α-hydroxylase and 17,20-desmolase are associated with primary amenorrhea, sexual infantilism, and hypertension.¹ The impaired steroidogenesis results in loss of negative feedback and elevation in the endogenous FSH. This in turn has been implicated in recruiting larger cohorts of follicles, resulting in an accelerated exhaustion of the oocyte complement.¹⁴^–¹⁶

HLA-DR3-linked predisposition to premature ovarian failure with autoimmune polyglandular endocrinopathies has been demonstrated.³⁹ Autoimmune polyglandular syndromes are a series of disorders characterized by autoimmunity against two or more endocrine organs. BPEI syndrome (blepharophimosis, ptosis, and epicanthus inversis), an autosomal dominant disorder mapped to chromosome 3q, is associated with development of premature ovarian failure.^40,⁴¹ Myotonia dystrophica, secondary to a mutation of a gene located on chromosome 19, may be associated with premature ovarian failure.⁴¹ Moreover, the genes FRAXA and POF1B have been implicated in premature ovarian failure.⁴² Autosomal disorders such as mutations of the phosphomannomutase 2 (PMM2) gene have been identified in patients with premature ovarian failure.⁴³ Perrault’s syndrome, with deafness and familial autosomal recessive premature ovarian failure, has also been described.⁴⁴

Sex Chromosome Abnormalities

Specific sex chromosome anomalies may be identified in some patients presenting with premature ovarian failure.⁴⁵ Among them, 45,X and 47,XXY are most prevalent, followed by variable mosaicism.⁴⁶ The X chromosome contains genes critical to ovarian function.

It is generally believed that the Y chromosome directs the indifferent gonad toward testicular differentiation and that differentiation toward ovarian differentiation requires less specific gene activation. It is clear that both X chromosomes are required to maintain the function of the ovary.

The critical region spans Xq13-26.¹ Proximal deletions (Xq13-21) can be associated with primary amenorrhea while the more distal ones are associated with premature ovarian failure. Genes termed POF1 and POF2 have been localized to Xq21.3-27 and Xq13.3-q21.1, respectively.¹ The age at menopause is significantly younger with the latter.

Deletions in these genes are typically not associated with short stature. Within the short arm of the X chromosome, some regions have been associated with risk for premature ovarian failure. The chance of having an abnormal karyotype increases with earlier age of onset of the ovarian failure.⁴⁵ A chromosomal analysis is recommended for patients younger than age 30 because of increased risk of a gonadal tumor associated with the presence of a Y chromosome.⁴⁷^–⁴⁹

Swyer syndrome, with 46,XY chromosome compliment and a uterus, may result from a defective Y chromosome and usually presents with primary amenorrhea. The frequency of Y chromosome material detected by polymerase chain reaction is high in Turner’s syndrome (12.2%), but the occurrence of a gonadal tumor among these Y-positive patients is low (7% to 10%).⁵⁰ It has been estimated that 75% of premature ovarian failure patients presenting with primary amenorrhea have a 45,X or mosaic chromosome patterns.⁵¹

Fragile X syndrome premutation carriers, typically with mental retardation and developmental delay, intention tremor, ataxia, or dementia, are at an increased risk for premature ovarian failure, with an incidence of 16% to 21%.⁵² A higher risk for premature ovarian failure (28%) has been proposed for carriers inheriting the premutation from the father, compared to a 4% risk when inherited from the mother.⁵³ Expansion of a triplet repeat within exon 1 of the FMR1 X-linked gene causes the fragile X syndrome. Expansions of between 50 and 200 repeats are premutations. Evidence suggests that female carriers of premutations in the FMR1 gene are at increased risk of premature ovarian failure. Although it is difficult to be obtain precise information, the risk has been reported to be between 22% and 26%.⁵⁴

Autoimmune Etiologies

Autoimmune premature ovarian failure can be isolated or part of the polyglandular autoimmune syndromes (see Table 20-1).^55,⁵⁶ These syndromes are associated with ovarian failure in more than 60% of patients. Polyglandular autoimmune syndrome type1 is rare, occurs before adulthood, and is inherited in an autosomal recessive manner; its components include hypoparathyroidism, mucocutaneous candidiasis, hypoadrenalism, and primary hypogonadism. The adrenal autoimmunity is directed against the side chain cleavage and the 17-hydroxylase enzymes. Polyglandular autoimmune syndrome type 2 is more common, usually occurs in adults, has a female preponderance, and has a polygenic inheritance related to HLA-DR3 and HLA-DR4; its components include adrenal insufficiency, autoimmune thyroid disease, type 1 diabetes mellitus, and gonadal failure. The adrenal defect involves antibodies to the enzyme 21-hydoxylase.

A spectrum of other autoimmune disorders has been recognized in patients with premature ovarian failure, including vitiligo, myasthenia gravis, Sjögren syndrome, systemic lupus erythematosus, celiac disease, rheumatoid arthritis, and pernicious anemia.

Histologic evidence of lymphocytic oophoritis has been demonstrated in 11% of patients with premature ovarian failure; 78% of these patients were positive for steroid cell antibodies, suggesting an immune-mediated insult to the ovaries.⁵⁷ The lympocytic infiltration seems to spare the primordial follicles. A loss of the regulatory/suppressive CD4+ cells may be the underlying mechanism for premature ovarian failure in patients with thymic aplasia, resulting in an exaggerated autoimmune damage to various organs, including the ovary.⁵⁸ Circulating immunoglobulins that inhibit the binding of FSH to its receptor have been described.⁵⁹

In a prospective clinical trial of 119 women with karyotypically normal spontaneous premature ovarian failure, testing for hypothyroidism (27%) and diabetes (3%) was judged to be worthwhile. It was suggested that tests for other possible associated diseases be based on associated clinical presentation.⁶⁰ Steroid cell autoantibodies seen in Addison’s disease may cross-react with the theca interna/granulosa layers of the ovarian follicles, and their presence is a marker for the association of Addison’s disease and premature ovarian failure. Steroidogenesis enzymes can be targets of autoantibodies. Three percent of women with premature ovarian failure develop adrenal insufficiency (a 300-fold increase compared with the general population). Symptoms could include anorexia, weight loss, vague abdominal pain, weakness, fatigue, salt craving, and skin hyperpigmentation.

The lack of consensus on ovary-specific antibodies as markers for ovarian autoimmunity has clinical and research consequences. Variations in detection of ovarian autoantibodies are likely to be due to study design elements such as antibody test format and antigen preparation, in addition to the multiplicity of intraovarian targets potentially involved in ovarian autoimmunity, including ovarian cellular elements and oocyte-related antigens.⁶¹ Many studies only assess one target antigen, leaving individuals with ovarian autoimmunity unidentified.

Infectious Agents

A rare type of infection related to premature ovarian failure is mumps oophoritis. It appears that this aberration in menstrual function and fertility may be related to the time during which the infection occurs as well as to the severity of the infection. In addition, it is apparent that mumps oophoritis may be a more frequent cause of premature ovarian failure than commonly suspected.^62,⁶³

Iatrogenic Etiologies

Chemotherapy

Many chemotherapeutic agents used for the treatment of malignancies are toxic to the ovaries and cause ovarian failure. Chemotherapy is associated with exaggerated attrition of ovarian follicles through alteration of DNA, direct destruction of dividing granulosa cells, and damage to the oocytes.^1,⁶⁴^–⁷³ These effects may be preventable, as discussed in the Management of Premature Ovarian Failure section in this chapter.

Radiation

The effect of radiation depends on age and the X-ray dose.^74,⁷⁵ Duration of time over which exposure occurs may also be important. Steroid levels begin to fall and gonadotropins rise within 2 weeks after radiation of the ovaries. Young women exposed to radiation are less likely to have immediate and permanent ovarian failure, possibly because of the higher number of oocytes present at younger ages.

The risk of premature ovarian failure can be reduced in women undergoing pelvic irradiation by laparoscopically transposing the ovaries out of the pelvis before radiation.⁷⁶ The risk does not appear to be reduced by treatment with hormone modulators before irradiation.⁷⁷

The sensitivity of the cells to the adverse influences is related to the nature of the agent, the dose, and the patient’s age at the time of exposure; the younger the patient, the lesser the likelihood of complete cessation of gonad function as an immediate sequel to therapy.^1,⁷⁸ The duration of exposure to toxic agents may also be relevant. Resumption of menses and pregnancy have been reported after radiotherapy and chemotherapy.⁷⁹