Premature Ovarian Failure

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Chapter 20 Premature Ovarian Failure

Khalid Ataya

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

Autoimmune

Isolated ovarian disorder

Polyglandular autoimmune syndromes 1 and 2

Infectious

Iatrogenic

Chemotherapy

Radiation

Repetitive ovarian surgery

Environmental toxins Idiopathic

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

Surgery

Surgical or vascular injury to the ovary may reduce the number of available ovarian follicles. Ovarian torsion and its effects on blood supply reduction may contribute to the damage. Operative laparoscopy has become a more commonly done procedure by an increasing number of surgical specialties. Direct surgical injury to the ovarian vessels within or outside the ovary can have deleterious effects.

Destruction of intraovarian lesions such as endometriomas or other ovarian cysts may reduce intraovarian regional blood supply, with resulting ischemia. Multiple procedures on the same ovary can have a negative cumulative effect. The intraovarian use of electrocautery and other tissue destruction modalities may reduce the number of viable ovarian follicles.

Environmental Toxins

Smoking, among other environmental factors, has been shown to accelerate the onset of menopause by approximately 2 years.⁸⁰

Idiopathic Etiologies

Many women with premature ovarian failure may have none of the above etiologies. Population-based studies have suggested an association between various epidemiologic parameters and risk of premature ovarian failure. A low socioeconomic status, a higher education level and nulliparity,⁸¹ a higher body mass index and anthropometric measurements have all been proposed risk factors for developing premature ovarian failure in different populations.⁸²

Premature Ovarian Failure and Fertility

It is important to appreciate that in premature ovarian failure, despite the occurrence of amenorrhea and elevation of the FSH levels, residual oocytes may still exist, albeit in significantly diminished numbers.¹ Therefore the term premature menopause is not correct. Residual follicles, when present, usually exhibit episodic function, as opposed to the virtually inert oocyte–granulosa units seen in age-appropriate menopause.⁸³ As many as 20% of women with premature ovarian failure will exhibit sporadic ovulatory cycles.⁸⁴ Indeed, pregnancies have been reported in up to 8% of patients.⁸⁵

DIAGNOSIS OF PREMATURE OVARIAN FAILURE

Premature ovarian failure should be suspected in any woman younger than age 40 who presents with either amenorrhea or signs of hypoestrogenemia and menstrual irregularity. These women may go through a normal puberty and a variable period of cyclic menses followed by oligomenorrhea and amenorrhea (Table 20-2). Therefore, premature ovarian failure should always be included in the differential diagnosis of anovulation.

Table 20-2 Potential Clinical Symptoms and Signs of Premature Ovarian Failure

Younger than age 40

Gynecologic history

Irregular menses or amenorrhea

Anovulation or oligo-ovulation

Premature ovarian failure

Personal history

Autoimmune disease

Mumps infection

Exposure to toxic agents (radiation, chemotherapy)

Postural dizziness and salt craving

Neurosensory deafness

Dry eyes

History and Physical Examination

History and physical examination may reveal symptoms and signs of estrogen deficiency, such as hot flashes and urogenital atrophy with attenuated vaginal rugae and scant cervical mucus. The underlying ovarian defect may be manifest at varying ages, depending on the number of functional follicles left in the ovaries.

The different symptoms may be regarded as phases in a process similar to perimenopausal change regardless of the actual age of the patient. If loss of follicles occurs rapidly before puberty, primary amenorrhea and lack of secondary sexual development ensue. The degree to which the adult phenotype develops and when the amenorrhea occurs depend on whether follicle loss took place before, during, or after puberty.

Deafness can be suggestive of Perrault’s syndrome.⁴⁴ There also appears to be an association of premature ovarian failure with dry eye syndrome.⁸⁶ Family history of premature ovarian failure and familial mental retardation should be obtained. The risk of FMR1 mutation in patients with premature ovarian failure and no family history is approximately 6%. In patients with a family history of premature ovarian failure the risk is higher. History of mumps infection should be obtained. Exposure to radiation, chemotherapy, tobacco products, and other environmental toxins may result in accelerated ovarian follicular loss and should be noted. All prior ovarian surgeries should be documented. Fatigue, weight loss, anorexia, nausea, postural dizziness, and salt craving may suggest adrenal insufficiency.

Most patients have normal results on physical examination except for urogenital atrophy (Table 20-3). However, features of Turner’s syndrome, such as short stature, low posterior hairline, high arched palate, shield chest with widely spaced nipples, and short fourth and fifth metacarpals, should be sought. Evidence of possible associated autoimmune diseases such as ptosis and goiter should be pursued. Evaluation for neurosensory deafness and a detailed eye examination should be considered. Hyperpigmentation, postural hypotension, and vitiligo may be signs of associated adrenal disease.

Table 20-3 Possible Physical Findings in Premature Ovarian Failure

Short stature

Low posterior hairline

High arched palate

Shield chest

Widely spaced nipples

Short 4th and 5th metacarpal

Absence of vaginal rugae

Ptosis

Goiter

Skin hyperpigmentation

Postural hypotension

Vitiligo

Laboratory Evaluation

Menopausal serum FSH levels (>40 IU/L) on at least two occasions in a woman younger than age 40 are sufficient for the diagnosis of premature ovarian failure. Any woman with irregular menses for 3 consecutive months requires FSH, estradiol, prolactin, and thyrotropin measurements to rule out premature ovarian failure among other hormonal etiologies.

The progestin challenge test can be misleading in the early stages of premature ovarian failure. Significant levels of circulating estradiol can be present in women with little residual ovarian function.

Once premature ovarian failure is diagnosed, the patient should be evaluated for associated autoimmune disorders. Testing for antiovarian antibodies is considered to be unreliable at this time. Far more critical is testing for antiadrenal antibodies. If they are positive further testing of adrenal function is necessary (Table 20-4). The most sensitive test is the corticotropin stimulation test.

Antiadrenal antibodies (adrenal disease)

If positive, screen with corticotropin stimulation test

Fasting glucose (diabetes) Thyrotropin T4, antithyroid antibodies (thyroid disease) Calcium and phosphorus (parathyroid disease) Complete blood count (pernicious anemia)

Women with premature ovarian failure are at increased risk of autoimmune thyroid disease. For this reason, thyrotropin, T₄, and thyroid peroxidase autoantibodies should be obtained. Other tests for autoimmune disease include a sedimentation rate, complete blood count with differential, antinuclear antibody, and rheumatoid factor.

Other tests to consider under specific circumstances are a fasting glucose test to check for diabetes mellitus, calcium and phosphorus to exclude hypoparathyroidism, pregnenolone to evaluate 17-hydroxylase deficiency in sexually infantile hypertensive women, and galactose-1-phosphate to evaluate for galactosemia. A karyotype is necessary to evaluate X chromosome abnormalities and the presence of Y chromosome material. Although most cases occur before age 30, some authorities feel that all patients with premature ovarian failure should have a karyotype. Testing for premutation in the FMR1 gene would identify fragile X pedigrees.

In amenorrheic women who desire fertility, FSH, LH, and estradiol should be measured weekly for a month to detect any remaining ovarian follicular activity. The lack of significant rise of estradiol or decrease of FSH suggests irreversible ovarian failure, especially in the absence of any demonstrable antral follicles on ultrasound.⁸²

Alternatively, indirect information about the remaining ovarian reserve of follicles in women with some menstrual function may be obtained by measuring day 3 FSH and estradiol,^23,⁸⁷^–⁸⁹ performing a clomiphene challenge test,⁹⁰ and obtaining an ultrasonographic antral follicle count.⁹¹

Ovarian Biopsies

Ovarian biopsies are not necessary for clinical care. When done as part of a research protocol in women with premature ovarian failure, ovarian biopsies show either no follicles or a small number of follicles, sometimes with lymphocytic perifollicular infiltration consistent with an autoimmune process. In patients with the resistant ovary syndrome, many small follicles are found with little progress in folliculogenesis.⁸²

Imaging

In primary amenorrhea associated with hypergonadotropic hypogonadism and sexual infantilism, the ovarian remnants may exist as streaks, and transvaginal ultrasonography usually cannot detect any ovaries. Follicular cysts and pregnancies have been demonstrated in a subset of patients with high gonadotropin levels and menstrual irregularities diagnosed with premature ovarian failure.

Pelvic ultrasonography for antral follicle count has been used as an indirect indicator of ovarian follicle reserve.⁹¹ Antral follicles will appear as round or oval echo-free structures up to 5 to 10 mm in diameter. Pelvic ultrasonography will sometimes reveal remaining follicles in patients 6 years after a diagnosis.⁹⁰

Bone density should be performed as a baseline and as frequently as needed thereafter. However, it is critical to understand that the results need to be interpreted in light of the patient’s age (see Chapters 24 and 25). Treatment protocols may need to be modified to ensure that osteoporosis does not become a problem.

MANAGEMENT OF PREMATURE OVARIAN FAILURE

Prevention

Probably the most important lifestyle event for primary prevention is to stop smoking. Very little can be done to prevent premature ovarian failure caused by cytogenetic or infectious etiologies. Laparoscopic transposition of ovaries out of the pelvis before radiation reduces the risk of premature ovarian failure.^92,⁷⁶ This risk does not appear reduced by prior treatment with hormone modulators.⁷⁷

Predictable ovarian failure related to premature ovarian aging, such as with familial premature ovarian failure, may allow several preventive intervention options, most of which remain experimental at this time. For the 10% of women in the general population who are expected to become menopausal by age 45, the critical point of 25,000 resting follicles would probably be reached 13 years earlier. By age 32, these women would begin a rapid decline of fertility and possibly have total loss of fertility by age 36. In the years following the diagnosis at age 32 or younger, these women will have a reproductive potential similar to a 37-year-old woman and could experience increased incidence of dizygotic twinning,⁹³^–⁹⁵ increased incidence of aneuploidy^88,⁹⁶ and miscarriage,⁸⁹ subfertility,^90,⁹⁷ and a relatively poor response to ovarian stimulation.

Under this scenario of fixed time intervals between premenopausal reproductive milestones, menstrual cycles may continue to be regular for 6 to 8 more years following the diagnosis of reduced ovarian follicular reserve.^9,^10,^16,⁹⁸^–¹⁰¹ The diagnosis may be suspected by finding reduced antral follicle counts,^18–21,⁸⁷ elevated FSH on the third day of menses and after a clomiphene challenge test, and lower inhibin B levels.^23,⁸⁸^–⁹⁰ There seems to be a large overlap between basal FSH levels of older and younger women, however.¹⁰² Variants of FSH receptor genotype were associated with different basal FSH levels and variable responses to ovarian stimulation with gonadotropins. A mildly elevated basal FSH level does not necessarily mean early ovarian aging.^98,¹⁰³^–¹⁰⁵ Serum antimüllerian hormone has been suggested as another marker.^106,¹⁰⁷ It is hoped that “DNA fingerprints” that identify women with a genetic predisposition to early ovarian aging may become available.¹⁰ For women at risk, it is wise to advise them to complete their families as soon as possible. For socioeconomic and career priority reasons, some of these women may elect to postpone childbearing, however.

The details of surgical and nonsurgical options to preserve oocytes from being prematurely lost because of chemotherapy or premature ovarian aging are presented elsewhere in this book (see Chapter 32). The surgical approach involves excising some ovarian tissue followed by variable laboratory manipulation of the tissue. The birth of a healthy child from a frozen-thawed ovarian autograft in a 32-year-old woman with Hodgkin’s disease was reported recently.¹⁰⁷ Crucial factors in the rapid depletion of the primordial follicles observed in the transplant can be attributed to the still rudimentary technical steps of tissue harvesting, preparation, and localization of the graft. The risk of reintroducing cancer cells through the grafted ovarian tissue calls for an extremely careful selection of patients for this still experimental treatment.¹⁰⁸

The nonsurgical approach involves the use of hormonal manipulation to halt follicle depletion related to age or chemotherapy.^72,^73,¹⁰⁹^–¹¹² Nuclear cloning techniques could also generate oocytes from stem cells.¹¹³ The recently described oogonia stem cells in postnatal ovaries, if confirmed, could also open new horizons in this arena.¹¹⁴ The nonsurgical approach seems to be preferred by a larger number of young American women.¹¹⁴

Counseling

Patients determined to have premature ovarian failure should receive psychological, endocrinologic, and genetic counseling regarding the implications of their disease (Table 20-5).

Table 20-5 Premature Ovarian Failure Patients Referred for Genetic Counseling

Women with a family history of premature ovarian failure

Women with premature ovarian failure and a chromosomal abnormality

Women with premature ovarian failure and family history of mental retardation

Fertility Prognosis

Pregnancies have been reported in women with premature ovarian failure and high gonadotropin levels.¹¹⁵ It has been suggested that approximately one half of young women who have 46,XX spontaneous premature ovarian failure have ovarian follicles remaining in the ovary.¹¹⁶ These follicles function intermittently and unpredictably, and pregnancies can occur without intervention. At present, there are no proven therapies that will improve follicular function for these women. Premature ovarian failure patients still have a 5% to 10% chance to conceive after diagnosis.¹¹⁷

A randomized trial of hormone replacement in this setting showed that folliculogenesis occurred often but was less frequently followed by ovulation and even less frequently by pregnancy (up to 14%). Controlled trials have failed to demonstrate any success with any treatment in excess of the placebo.^118,¹¹⁹ Estrogen therapy did not improve the rate of folliculogenesis, ovulation, or pregnancy.¹¹⁸ The clinician should inform premature ovarian failure patients that there is a small likelihood of spontaneous pregnancy. Women desirous of achieving pregnancy are still best served by donor oocytes¹²⁰; an increased susceptibility to poor ovarian response exists when utilizing a related donor. It has been suggested that corticosteroid treatment may result in normalization of serum gonadotropins, increasing serum estradiol, ultrasonographic evidence of follicular growth, and conception, especially in women with premature ovarian failure associated with autoimmune disease.¹²¹ However, this treatment is considered experimental.

Hormone Replacement

The diagnosis of premature ovarian failure results in multiple profound ramifications, including psychological devastation,¹²² multisystem effects of estrogen deprivation such as osteoporosis,^123,¹²⁴ cardiovascular morbidity,^123,¹²⁵ depression, and cognitive difficulties.¹²⁶ Bone mineral density scores of approximately 1 standard deviation below the mean for age-comparable women have been demonstrated in patients with premature ovarian failure, despite taking estrogen replacement,¹ with a 2.6-fold increase in risk for hip fractures.

A higher mortality rate in association with diminishing age of menses cessation has been reported.¹²⁷ Snowdown and colleagues¹²⁷ found an odds ratio (OR) for mortality of 1.95 (CI, 1.24–3.07) for women developing premature ovarian failure. The excess mortality was associated with coronary artery disease and stroke. This persists despite use of estrogen replacement, with the OR for mortality being 3.33 (CI, 1.14–9.72) for patients ever using estrogen replacement therapy. Women in specific pathophysiological subgroups of premature ovarian failure (i.e., autoimmune, X chromosome-related) may be more susceptible to vascular disease on the basis of the underlying defect that caused the premature ovarian failure. Other women with premature ovarian failure (i.e., chemotherapy- or radiation-induced) may be more prone to long-term diseases and mortality by virtue of their primary disease that necessitated chemoradiation therapy.

Hormone replacement therapy, as an “antidote” for aging in women, is becoming a less compelling option as results accumulate and alternative nonhormonal medications demonstrate efficacy against the common diseases of aging. The safety, dose, administration route, and appropriateness of selection criteria of hormonal and nonhormonal interventions are discussed elsewhere in this book and for the most part are applicable to premature ovarian failure. Typically these patients require higher doses, such as 100 μg estradiol transdermal patch to give a serum estradiol level of 100 pg/mL. Cyclic progesterone is also required. Alternatively, because of the relatively younger group age and the possibility of unpredictable ovulation, the use of birth control pills may be appropriate if the patient is not interested in pregnancy. Adequate calcium intake, vitamin D, and exercise should be reinforced. In general, treatment of premature ovarian failure should be directed toward its specific cause, if possible. Associated disease processes affecting other glands or tissues (such as thyroid and adrenals) should be addressed as well.