Hypergonadotropic hypogonadism

CURRENT DEVELOPMENTS

Hypergonadotropic CHAD HOLLY

I.

FRIEDMAN, BARROWS,

MOON

H.

Columbus,

Ohio

KIM,

hypogonadism

M.D. M.D.

M.D.

Etiologic factors in hypergonadotropic hypogonadism are discussed. On the basis of these data a classification system is proposed for women with hypergonadotropic hypogonadism to be used in future investigations of the natural history of this disorder. The classification system can also be used in attempts at therapeutic intervention in these women. Recommendations for clinical management and future studies of women with hypergonadotropic hypogonadism are provided. (AM. J. OBSTET. GYNECOL. 145:360, 1983.)

PREMATURE MENOPAUSE isusedtodescribeaclinical state of permanent ovarian failure occurring after menarche but before the normal menopausal age. It has arbitrarily been defined as occurring before age 35 or 40; both ages are 2 SD away from the mean age of menopause of 51 years. ‘3 2 Primary ovarian failure, a still more general term, describes the lack of ovarian function in response to gonadotropin stimulation at any age. Included in the category of primary ovarian failure are premature menopause, mixed gonadal dysgenesis, pure gonadal dysgenesis, insensitive ovary syndrome, and the gonadotropin-resistant ovary syndrome. To patients desiring fertility all of these diagnoses imply a disease state in which no reliable therapeutic intervention has been found. What proportion of patients with primary ovarian failure represents variants of normal physiology or composites of pathologic events remains in question. Chromosomai aberrations are common in patients with primary amenorrhea but play a lesser role in cases of secondary amenorrhea.

From the Department Ohio State University

of Obstetrics Hospitals.

and Gynecology, The

Reprint requests: Chad I. Friednuzn, M.D., O.S.U. Hospitals, 410 W. 10th Ave., Columbus, Ohio 43210.

Immunologic, iatrogenic, heritable, and infectious etiologies have all been suspect in patients with premature menopause. However, in the majority of patients with secondary amenorrhea and ovarian failure the cause remains unresolved. The intent of this review is to examine the clinical spectrum of primary ovarian failure in women with a 46,Xx karyotype. An attempt is made to remodel a now complicated classification system. The clinical management and prognosis of primary ovarian failure are discussed. The data base consists of a review of published literature as well as experience with 25 patients with primary ovarian failure and a 46,Xx karyotype seen during the past 4 years. Historically, before the development of an assay for gonadotropins, the diagnosis of premature menopause was made on the basis of clinical signs and symptoms alone. With the use of basal body temperatures, colpocytologic examinations, and endometrial biopsies, Arias,3 in 1950, was able to document anovulation and estrogen deficiency in 20 young women with secondary amenorrhea and hot flushes. Perloff and Schneeberg,’ in 1957, described 29 young women with a “premature climacterium” and confirmed their clinical presentation by demonstrating elevated biologically active urinary gonadotropin levels. As urinary and serum assays became widely available, emphasis was placed on lab000%9378/83/030360+13$01.30/0

@ 1983TheC.V.MosbyCo.

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Hypergonadotropic

Table I. Summary follicular

of some of the clinical

findings

reported

from

Vammotor

syrnfitom.5

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361

seven series of premature

depletion

&rim Starup and Sele4 De Moraes-Ruehsen and and Jones5 Keettel and Bradbury Behrman’ Zarate et alR Vaida et aLs Rebar et aLi Present series

Mean

Mean

No. of patients

age at menopause

! Secondary

infbtility

Family history f%J

(%)

24 20

22 23

50 80

8 10

212 NS

4-8 10

12 16 8 12 26 25

25 23 24 30 NS 23

42 38 50 :z

58 37 25 33 19 28

NS 5/7 NS NS NS 6110

0 NS 12.5 NS NS 8

Patients with gonadotropin-resistant lation. NS = Not stated.

68

(%)

Paritylffav&&

(Yd

ovary syndrome and abnormal karyotypes, when known, were excluded from the caku-

oratory findings rather than clinical presentation. The diagnosis of premature menopause was broadened to include women with secondary amenorrhea and elevated serum or urinary gonadotropin concentrations even in the absence of a clinically evident estrogen deficiency. With patients having abnormal chromosomal complements excluded, 4.8% of patients with secondary amenorrhea before age 30 were diagnosed as having primary ovarian failure in Starup and Sele’s4 series. De Moraes-Ruehsen and Jones5 reported an incidence of 6.6% in patients under 35 years of age with amenorrhea. Hormonal studies of patients with premature menopause are similar to those in patients undergoing a normal menopause. Elevated gonadotropin serum concentrations and low serum estradiol concentrations are found with ovarian failure. When hormonal markers are used to diagnose premature ovarian failure, vasomotor symptoms are found in only about 60% of patients with premature menopause.*, 6 Atrophic changes are rarely present at the time of diagnosis, although underdeveloped secondary sex characteristics may be seen with subjects developing ovarian failure shortly after menarche. When these subjects are considered as a group, menarche occurs at the average age of occurrence in the normal population, but the incidence of delayed menarche may be increased in patients with primary ovarian failure. ‘9 5 Fertility is limited in these patients predominantly by the reduced number of ovulatory cycles. It is unclear whether a higher incidence of clinical abortions is also observed as is found in older women approaching termination of reproductive function.6 Table I reviews some of the presenting symptoms and reproductive performance of women with primary ovarian failure and a normal chromosomal complement. With the use of repetitive serum concentrations of

follicle-stimulating hormone (FSH), luteinizing hormone (LH), and the measurement of serum estrogen levels to corroborate the clinical impression of menopause, several interesting laboratory findings emerged. A perimenopausal transition was documented, as has been shown in the normal climacteric.“” Vaidya and associates9 found, in five of 12 women with histologic evidence of oocyte depletion and amenorrhea, that normal estrogen levels were associated with elevated FSH serum levels. Fig. 1 shows the serum concentrations of FSH and estradiol (E,) of five women during 6 to 12 months of observation. Menopausal serum concentrations of immunologic FSH are seen despite intact negative feedback regulation. Follicular activity is assumed by the finding of midfollicular serum concentrations of Et. Thus, the hormonal parameters used to define menopause are inadequate to presume complete loss of follicular function.12 As in the physiologic climacteric the last remaining follicles in patients with premature menopause are hypothesized to be relatively resistant to gonadotropins, requiring higher concentrations for induction of follicular growth and E, synthesis. Shangold and associatesI coined the term insensitive ovary syndrome to describe this entity. In addition to symptoms and hormonal parameters to confirm a clinical diagnosis of premature menopause, ovarian visualization and biopsies have been used. In the majority of these cases atrophic ovaries devoid of follicles were found. However, not all of the ovaries appeared typical of the normal menopausal ovary. Many of the ovaries were of normal size with rare developing follicles or a corpus luteum, a finding in conflict with the clinical impression, although possibly consistent with findings during the perimenopause. ** *, 6 Other ovaries were described as “fatty” and spindle shaped, much reduced in size.]“ Still other authors described rudimentary streak gonads.‘ss I6

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February Am. J. Obstet.

CASE

CASE

I

0

3

6

9

12

0

MONTHS miu/ml

1, 1983 Gynecol.

2

3

6 MONTHS &ml .300

9

12

100

CASE mum

4

CASE 1 w/ml

I

miwinl

,

5 .

pg/ml

IOO-

100

4 3

6 MONTHS

9

I2 MONTHS

Fig. 1. FSH and E2 serum concentrations in five subjects diagnosed as having premature over an observation period of 6 months to 1 year.

The streaked gonad was believed characteristic of patients with a separate entity, gonadal dysgenesis. Included in this group were patients with Turner’s syndrome (45,X), Swyer’s syndrome (46,XY), and 46,Xx pure gonadal dysgenesis. In contrast to patients with premature menopause, individuals with gonadal dysgenesis traditionally presented with primary amenorrhea and sexual infantilism. On the basis of morphologic and hormonal criteria the clinical entities of gonadal dysgenesis and premature menopause appear to overlap. Histologic examination of the ovary resulted in clear differentiation between the two distinct pathologic states occurring with hypergonadotroic hypogonadism and primary or secondary amenorrhea. In the majority of cases histologic examination revealed few or no follicles. The stroma was largely fibrosed and inactive as in

menopause

the postmenopausal ovary. A much smaller group of patients demonstrated numerous primordial follicles without maturation beyond the antral stage.4* I49 r7 These findings, described initially by Kinch and associateP and later by Jones and De Moraes-Ruehsen,” became known as the gonadotropin-resistant ovary syndrome. While it is clinically distinct from premature menopause, its clinical presentation is identical.

Clasdticetlon The terminology used to categorize patients with primary ovarian failure has led to considerable confusion when etiologic factors are discussed. Shown in Fig. 2 is our proposed classification of primary ovarian failure. The initial division is between those individuals with an intact number of immature follicles (gonadotropin-resistant ovary syndrome) and women with

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Hypergonadotropic

Gonadotropin-resistad / Immunologic ????? Idiopathic

ovary syndrome

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Premature follicular depletion \ / 46,Xx Chmmosomally abnormal 45,X; 45,X/46,XX

Familial Immlmologic Iatrogkc Infectious secolldary to systemic disease Idiopathic

Fig. 2. Proposedclassification for primary ovarianfailure. premature follicular depletion. Hypergonadotropic subjectswith premature follicular depletion are initially divided dependent on their chromosomalcomplement. Traditional etiologic causesare then used for further categorization of subjectswith a 46,Xx karyotype and documented follicular depletion. Many subjectswill fall in the category of idiopathic follicular depletion where no etiology can readily be determined. Patients previously diagnosedashaving 46,Xx pure gonadal dysgenesis,premature menopause,and the insensitive ovary syndrome are all classified as demonstrating chromosomally competent premature follicular depletion. Patients with a 46,Xx karyotype and streaked gonadsare not separately classified.They are assumedto have possessed a normal complement of follicular units during fetal life, which underwent rapid atresia similar to that in patients with Turner’s syndrome.‘* If this analogy is correct, a limited number of functional follicles might survive until the time of puberty.lg* *O This hypothesis is supported by McDonough and associates’lsreport of 27 patients with “chromosomally competent ovarian failure.” While rudimentary streaked gonads were found in 25 of these subjects,40% had evidence of follicular function, early development of secondary sex characteristics,and spontaneousmenses. I8alsodescribedthree women Emperaire and associates with rudimentary streak gonads, secondary amenorrhea, and normal secondary sex characteristics. Further support for the grouping of these two clinical entities comesfrom reports of the occurrence of premature menopauseand gonadal dysgenesiswithin the samefamilies.*l, 22The rudimentary streak is not an appropriate distinction to separate 46,Xx gonadal dysgenesislogically from other categories of chromosomally competent premature follicular depletion. We agree with Kinch and associates’*that an abnormal sex chromosome complement is a prerequisite for the diagnosisof gonadal dysgenesis. While descriptive, a separateclassificationfor the in-

sensitive ovary syndrome is not warranted. Sporadic ovulation in the presence of elevated gonadotropin levels is a physiologic occurrence seen in association with extensive follicular depletion during the “perimenopausaltransition.” The inclusion of the insensitive ovary syndrome into a classificationwould imply the ability to differentiate complete foilicuiar depletion. No hormonal studiesor ovarian biopsy procedures short of oophorectomy are capableof identification of complete follicular depletion. With the limitations of ovarian biopsiesconsidered the proposed classification allows for a clear division into two groups: (1) those with numerous immature follicles or the gonadotropin-resistant ovary syndrome and (2) those with a decreased number of follicles or premature follicular depletion. At present further categorization of women with chromosomally competent premature follicular depletion is basedon traditional etiologic classification. Genetic etiology. Almost 10% of women with premature ovarian failure have a mother, aunt, or grandmother who experienced cessationof mensesin her late 20s or early ~OS.~* 5** A random positive family history provides only an indirect clue that oocyte depletion may be an inherited disorder. Familial histories of subjectspreviously classifiedas having “premature menopause” have suggestedeither an autosomal recessiveor a dominant inheritance.*‘* 23*24In a review of 91 casesof “46,Xx pure gonadal dysgenesis,”14 familial aggregateswere described.25In each aggregate, sibs were the only relatives affected, and in three families parents were consanguineous,implicating an autosoma1recessivegene. In other families this hasalsobeen associatedwith syndromesin which direct inheritance is well documented, as in Albright’s hereditary osteodystrophy syndrome, which has a presumed X-linked dominant mode of inheritance.25 In several families primary ovarian failure and neurosensory deafness have been reported .26In three other families, each apparently unique, ovarian failure wasassociatedwith a specific pattern of somatic abnormalities, none associ-

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ated with the Turner stigmasz6 In each family the anomalies were different, thus implicating genetic heterogeneity or pleiotropy for the gene causing ovarian failure and somatic anomalies or implicating a separate mutation occurring coincidentally. In cases of inheritance of somatic anomalies in association with premature follicular depletion, the presence of a genetic etiology seems clear. A report of monozygotic twins who were discordant for ovarian failure, however, emphasizes the difficulties in distinguishing genetic from environmental factors in individual cases?’ Immunologic etiology. In 1963, Vallotton and Forbes** reported on the existence of human serum antibodies to rabbit ova. While the study was unable to be confirmed, it sparked a search for immunologic causes of ovarian failure. Turkington and Lebovitzzg published a series, in 1967, and reported that up to 23% of their patients with idiopathic Addison’s disease had premature gonadal failure. Irvine and Chan,30 studying 77 female patients with idiopathic adrenal insufficiency, found only six patients with primary ovarian failure prior to age 35. However, of these six patients, five subjects had IgG antibodies to theta interna cells, as demonstrated by indirect immunofluorescence. Only one of the five patients reported on by Irvine and Chan30 had antibodies to rabbit ova, in contrast to the report by Vallotton and Forbes. That the theta interna antibodies are cross reactive with adrenal tissue in patients with ovarian failure and Addison’s disease has been confirmed by Elder and associates3’ In addition to Addison’s disease, numerous other immune disorders have been found in association with premature follicular depletion, i.e., Hashimoto’s thyroiditis, lupus erythematosus, myasthenia gravis, idiopathic thrombocytopenic purpura, hypoparathyroidism, and systemic candidiasis.*z 32-35 De MoraesRuehsen and associates33 attempted to assess the incidence of autohomologous antibodies in patients with premature hypergonadotropic hypogonadism with and without associated autoimmune disorders. A high incidence of such antibodies was found in women displaying two or more concurrent glandular disorders. Surprisingly, in patients with just ovarian failure, an increased incidence of thyroid and gastric parietal cell antibodies was detected. Our own findings support this observation.36 While a high prevalence of autohomologous antibodies can be found in women with premature follicular depletion, the prognostic value of these findings remains unresolved. Coulam and Ryan3’ studied 15 hypergonadotropic patients under the age of 35 with normal karyotypes. To detect ovarian antibodies they used a labeled ho-

February Am. J. Obstet.

1, 1983 Cvnecol.

mogenized ovarian pellet incubated with serum and an anti-IgG antibody. A statistically significant elevation of protein binding was found in patients with premature menopause, implying the presence of ovarian antibodies in the serum. The specificity of the antibody was not confirmed and values that overlapped with those of normal postmenopausal patients were found. The concept of autoimmunity as a cause of ovarian failure is based on two points, the finding of ovarian antibodies and the association with other disease believed to be autoimmune in etiology. Some of the inadequacies of this contention should be acknowledged. The presence of ovarian IgG antibodies is not sufficient to implicate them as the cause of follicular depletion. Humoral antibodies are generally not cytotoxic. Tissue destruction from a nonimmune cause mav allow an underlying defect in self-recognition to become manifest, producing autohomologous antibodies. McNatty and associates,38 attempting to demonstrate a causal role, studied the effect of ovarian antibodies on granulosa cells grown in culture. When serum containing corpus luteum-adrenal antibodies was added to the tissue media in the presence of complement, granulosa cell destruction was evident. The relationship of this single report to other cases of ovarian failure believed to be of autoimmune etiology requires further substantiation. Another possible immunologic cause for ovarian failure has been reported by Caldwell and associates,3s who found biologically active antibodies to purified LH receptors. It is hypothesized that excessive stimulation of ovarian follicles might lead to premature follicular depletion. 35 The report by Austin and associates’O and our own unpublished data would suggest that the incidence of these antibodies is low. In contrast to an autoimmune phenomenon, decreased cell-mediated immunity was found by Wilson and associatePI in patients with polyglandular failure, including ovarian failure. This finding implies that patients with multiple glandular failure may have a predisposition to pathogenic infection, rather than possess a hyperimmune system. Following damage to endocrine glands, antibodies to the damaged tissue are produced. This is consistent with the association of candidiasis and polyendocrinopathies and the proposed role of coxsackievirus B4 in diabetes.42 The occurrence of ataxia-telangiectasia syndrome with ovarian failure also suggests that a defective immune response may lead to ovarian failure.& Further support for this hypothesis is the preliminary report that a significant proportion of women with premature follicular depletion have depressed T-lymphocyte helper/suppressor ratios.36 It is apparent that further study of the immunologic factors

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involved in premature follicular depletion may be of major importance to the overall well-being of such patients. Iatrogenic causes. Radiation is capable of producing premature ovarian failure. Peck and associates,44 in 1940, reported that a dose of 500 “tissue roentgens” would castrate 90% of female patients. Thomas and associates45 observed women of reproductive age who received 150 to 3,500 rads to the ovaries. With low-dose exposure the subjects became amenorrheic but menses returned within a few months. With exposures of 500 to 3,500 rads to the ovaries, nine of 12 subjects demonstrated persistent hypergonadotropic hypogonadism. One subject was amenorrheic for 2 years and had confirmed hypergonadotropic hypogonadism. Menses later resumed and serum concentrations of LH returned to normal. Serum FSH concentrations remained elevated but were no longer in the castrate level. The remaining patient was amenorrheic for 2 years and then became pregnant; no gonadotropin levels were obtained. It was suggested that with further observation conversion to eugonadotropism might be found in more subjects treated with intermediate doses of radiation.“3 The role of chemotherapy as a cause of hypergonadotropic hypogonadism has been difficult to study because of multiple drug regimens, prior use of other treatment modalities, and other side effects associated with chemotherapy (i.e., weight loss). One of the earliest chemotherapeutic drugs studied was busulfan.4” Hypergonadotropism has been well documented following the use of busulfan. In rats busulfan administration during pregnancy is found to cause selective disappearance of fetal oocytes. A similar observation has been reported in rnamd7 Another alkylating agent, cyclophosphamide, is also associated with ovarian failure. Warne and associates,48 studying women of reproductive age on a regimen of cyclophosphamide with dosages between 50 and 200 mg/day for a duration of 1 to 33 months, found 18 of 21 patients to be amenorrheic. Two patients were pregnant; the remaining 19 patients were all hypergonadotropic, 17 being in the castrate range. In four of six hypergonadotropic patients undergoing ovarian biopsy, no ova were found, and all specimens failed to show follicular maturation. One hypergonadotropic subject’s ovarian biopsy showed decreased ova and maturational arrest. Twenty-six months later she regained normal ovulatory menstrual cycles after stopping treatment. Treatment with similar daily dosages but for shorter durations has been associated with amenorrhea during treatment with subsequent return of menses following discontinuation.4g

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Animal studies have suggested that prolonged exposure to low-dose environmental toxins may be another cause of ovarian failure. Mattisonso studied the effects in mice of three polycyclic aromatic hydrocarbons found in cigarette smoke-benzo-a-pyrene, S-methyl cholanthrene, and 7,12-dimethylbenz(cujanthracene (DMBA). The first two agents were capable of dramatically reducing the number of primary and primordial follicles without demonstrable effects on the more mature follicles. DMBA destroyed primary and primordial follicles but was also toxic to the mature graafian follicle. This study by Mattison lends support to the epidemologic study reported by Jick and associates,j’ in which an inverse relationship between the age of menopause and number of cigarette pack years was found. Citral, a food and cosmetic additive, has been shown to cause a similar depletion of ovarian follicles in rats.52 Citral is hypothesized to be toxic to the ovum with little influence on the steroid-producing cells of the follicle. Destruction of the ovum in immature follicles results in follicular depletion. Low levels of exposure to environmental toxins causing accelerated follicular depletion without acutely affecting ovarian steroid production would make clinical detection extremely difficult. Several years would likely intervene between chemical exposure and the diagnosis of premature follicular depletion. Much more work with environmental toxins and therr effects on reproduction is required. Infections. Despite the ovary’s frequent involvement in pelvic infections, ovarian function rarely appears to be permanently compromised. Mumps oophoritis is the most common infectious disease believed responsible for ovarian failure.” Five percent of female patients developing mumps are estimated to have gonadal involvement.j3 Subjects exposed during puberty are believed most susceptible to development of ovarian failure after mumps oophoritis. Systemic diseases. Mucopolysaccharidosis and galactosemia have been associated with premature follicular depletion? jj All are believed to cause follicle destruction from the accumulation of toxic substances within the ovary. In women with galactosemia ovarian failure appears common. In contrast, men generally retain their fertility. Gonadotropin-resistant ovary syndrome. Premature follicular depletion is thought to be a syndrome of rapid follicular atresia. In contrast, the patient with amenorrhea, elevated gonadotropin levels, and a biopsy revealing a normal complement of immature follicles in the ovary presents an interesting dilemma. One must explain the inactivity of apparently normal folli-

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cles in the face of markedly elevated immunologic and biologic serum gonadotropin concentrations. The gonadotropin-resistant ovary syndrome may be defined by the following criteria: (1) primary amenorrhea or secondary amenorrhea before the age of 30; (2) a normal chromosomal complement of 46,Xx; (3) increased endogenous production of FSH and LH; (4) presence of numerous morphologically normal, unstimulated ovarian follicles; (5) hyposensitivity of the ovarian follicles even to excessive stimulation with exogenous human gonadotropins.56 In 19 documented cases fulfilling the first four criteria of the gonadotropin-resistant ovary syndrome *, 14, 17p5*65 primary amenorrhea was seen in six patienb. Of the 13 women presenting with secondary amenorrhea, the age of onset of amenorrhea ranged from 13 to 25 years. In one patient with primary amenorrhea, immature secondary sex characteristics were found.57 In all other women, secondary sex characteristics were noted to be normally developed even in the presence of primary amenorrhea. Several of the patients were noted to have atrophic vaginal changes associated with a hypoplastic uterus and nonpalpable ovaries on pelvic examination. Serum concentrations of Ez were low or appropriate for the early or middle follicular phase. Mild facial hirsutism was reported in two patients and virilization occurred in one patient.58* 61, 62 Only three of the patients noted hot flushes; these patients had presented with secondary amenorrhea.2* 61* 63 Only one of the 19 patients had been pregnant prior to the diagnosis. In this case amenorrhea ensued 4 years after a normal delivery.64 It is known that development of the primordial follicles can occur with minimal or no gonadotropin stimulation.66 Under normal conditions, the granulosa cells produce Ez, which further increases the number of FSH receptors found in the granulosa cells of primary follicles.67* 68 As FSH and Ez act together to produce LH receptors, antral formation occurs with further growth of the follicle, resulting in eventual atresia in the majority of follicles. The biopsy findings in patients with the gonadotropin-resistant ovary syndrome indicate an arrest following the very early development of the primordial follicles. The occasional antral formation is not easily explained but has also been observed in patients with Kallmann’s syndrome (anosmic hypogonadotropic eunuchoidism).66 In the gonadotropin-resistant ovary syndrome, arrested follicular development is not due to a biologically inactive FSH molecule, as demonstrated by bioassay. i4, I7 Similarly, the molecular weight of FSH in the subjects is similar to that of normal postmenopausal women. 61 In a few of the patients steroidogenesis can be inferred by the active follicular atre-

February Am. J. Ohstet.

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sia that was present. Theta cell luteinization and sporadic stromal hyperplasia, although not present in all biopsy specimens, are suggestive of LH activity.“, j*, 62 Occasional corpora albicantia, even in women presenting with primary amenorrhea, imply previous follicular maturation. These findings indicate that the ovaries may not always have been inactive. That these women had normal growth and normally developed secondary sexual characteristics is also indicative of prior steroidal activity. Little data are available as to the causes of the gonadotropin-resistant ovary syndrome. There are two case reports that imply an association between autoimmune disease and the resistant ovary syndrome. Irvine and Chan30 have described a patient with Addison’s disease, ovarian failure, and ovarian histologic findings consistent with this syndrome in a patient who had anti-theta interna antibodies. Board and associates* reported on a 22-year-old null&avid woman, with menarche at age 13, who had regular menses until oral contraceptives were begun at age 20. After discontinuing the oral contraceptives she became amenorrheic. Serum levels of FSH and LH were markedly elevated, and estrogen concentrations were almost undetectable. Ovarian biopsy revealed normal ovarian tissue with many primary follicles and one early developing follicle. About 2 years after the onset of amenorrhea, the patient experienced the first signs and symptoms of myasthenia gravis and was appropriately treated. Neither ovarian nor antinuclear antibodies could be detected in this patient. An immune phenomenon may be tenuously postulated from the report by Meldrum and associatess2 of a patient with the gonadotropin-resistant ovary syndrome who ovulated after a 7-day treatment with 2 mg of dexamethasone a day. Starup and Pedersen56 administered 25 mg of cortisone a day and were unable to alter the gonadal status of a patient fulfilling the criteria of the gonadotropin-resistant ovary syndrome. There appears no genetic basis for the gonadotropin-resistant ovary syndrome. The clinical presentation points to an acquired disease process. A disturbance in the FSH receptor or the translation of FSH receptor interaction could explain the histologic and hormonal findings. Prolactin has been thought to exert an antigonadotropic action on the ovarian follicles, but peripheral prolactin concentrations have not been found to be elevated. Neither have antibodies against LH or FSH been demonstrated.56* 61 What environmental factors could cause the gonadotropin-resistant ovary syndrome are unknown. Siris and associatesas have reported on a patient with chronic myelogenous leukemia treated with multiple chemotherapeutic agents who had

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Table II. Previous reproductive performances, ovarian biopsy findings, 13 pregnancies following the diagnosis of premature menopause series

Behrman? Brosens et a1.7’ Hammerstein and Rommle? Johnson and Peterson’* Polanskv et al.” Shangold et alI3 Shapiro and Rubin StarUp et al.*O Szlachter et alT6 Wright and JacobsT7 Present series

Ovarian biopq

Graviditylpri~

NS o/o NS o/o o/o o/o 2/l o/o o/o o/o l/O o/o 2/o

NS No follicles NS

1 Follicle seen grossly No follicles No follicles Not done Few follicles Not done Not done Not done No follicles Not done

a clinical and pathologic picture similar to the gonadotropin-resistant ovary syndrome. The pathophysiology of the gonadotropin-resistant ovary syndrome remains poorly understood.

Diagnosis Amenorrhea is the most common finding in ovarian failure. In patients with vasomotor symptoms or signs of estrogen deficiency the serum FSH concentration should be determined for evaluation of whether a hypergonadotropic state exists. Hypergonadotropism also exists in euestrogenic states as in the perimenopausal period. In these patients the diagnosis is often delayed. Almost 50% of the patients we have seen with hypergonadotropism and secondary amenorrhea bled or spotted in response to a progestin challenge (10 mg of medroxyprogesterone for 5 days orally or 50 to 100 mg of progesterone in oil intramuscularly). This apparent perimenopausal transition phase probably extends over several years. In our series oligomenorrhea preceded the diagnosis of premature follicular depletion by almost 4 years. In the absence of primary amenorrhea, delayed pubertal development, or vasomotor symptoms, we have restricted determination of a serum FSH concentration to subjects who do not have withdrawal bleeding or have only spotting following a progestin challenge. Serum FSH levels are also determined in any ovulatory patient considered for exogenous gonadotropin therapy. In view of the lack of reliable therapeutic modalities for patients with hypergonadotropism, routine screening in all oligoamenorrheic or amenorrheic subjects does not appear cost effective in clinical practice. However, in patients with vasomotor symptoms and oligoovulation undergoing attempts at induction of ovulation, the finding of a normal serum FSH concentration

and medication

367

used in

Treatment

NS Estrogen Spontaneous Gonadotrooins Estrogen ’ Estrogen Estrogen Estrogen and Estrogen Estrogen Spontaneous Estrogen Spontaneous

hypogonadism

Duration from dzizgnosl~ to pregnanq

pregnancy

cortisone pregnancy pregnancy

is not sufficient to eliminate early ovarian failure as the underlying process. Repeated FSH determinations around the time of vasomotor symptoms may confirm the suspected diagnosis of limited ovarian reserve. Serum concentrations of LH are of minimal clinical use in evaluating for possible ovarian failure. Another test that has been utilized for this purpose is the gonadotropin-releasing hormone stimulation test.‘O The response is characterized by markedly increased concentrations of FSH after stimulation, similar to the results found during the physiologic perimenopausal transition period. This test is, however, of limited clinical value. The diagnosis of hypergonadotropism in a nulligravid woman younger than 35 should be followed by determination of a karyotype of either peripheral lymphocytes or skin fibroblasts. Patients with a 46,XY (Swyer’s syndrome) or 45,X/46,XY karyotype have been reported to undergo pubertal development in the absence of virilization.” The estrogen production was in association with gonadal tumors (gonadoblastomas). Therefore, prior menstruation is inadequate to assure the absence of Y chromatin material. Women with Y chromatin material should undergo gonadal extirpation because of the risk of neoplastic transformation. Patients seeking treatment for infertility with deficient X chromatin material should be spared the surgical evaluation necessary to distinguish the gonadotropinresistant ovary syndrome from premature follicular depletion. In patients with a normal karyotype, historical data are used to assess the likelihood of genetic, infectious, or iatrogenic causes. Suspicion of an immunologic cause of ovarian failure, however, relies predominantly on a laboratory evaluation. While there are numerous retrospective reports of ovarian failure preceding

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Hashimoto’s thyroiditis, idiopathic Addison’s disease, myasthenia gravis, and pernicous anemia, the prognostic value of antibody screening tests has not been established.2g* 30*33 At the present time for clinical management reliance is placed on clinical findings rather than a battery of tests. Only in women with a 46,Xx karyotype desiring a pregnancy are laparoscopy and ovarian biopsy considered. Our recommendations for ovarian visualization and biopsy pertain only for differentiation of the gonadotropin-resistant ovary syndrome from premature follicular depletion. Ovarian biopsies have not been of value in determining the response to induction of ovulation in patients with premature follicular depletion. l* Currently, attempts at induction of ovulation in hypergonadotropic women is an investigational procedure .

Treatment Prior to the widespread use of radioimmunoassay to measure serum FSH levels accurately, histologic documentation of oocyte depletion was used to diagnose ovarian failure because urinary gonadotropins were notoriously unreliable. It was assumed that attempts at ovarian stimulation were futile in patients lacking follicles on biopsy. Thus, very few patients with the diagnosis of ovarian failure received even a minimal attempt at ovulation induction. Despite the logic in this view, at least 13 spontaneous or induced pregnancies have been reported, as shown in Table II. Johnson and Peterson74 reported on a 26-year-old woman with hypergonadotropic hypogonadism, a familial history of premature menopause, and, on laparoscopy, “rugated, pearly, senescent ovaries.” During the fifth cycle of gonadotropin therapy she ovulated and conceived. The authors recommended empirical gonadotropin therapy in patients with premature ovarian failure desiring pregnancy. In the absence of ovarian follicles, exogenous gonadotropin therapy is unlikely to cause any significant morbidity. The extreme expense of such therapy, however, mandates a reasonable response rate. Others have tried stimulation without success. De Moraes-Ruehsen and Jones5 attempted induction of ovulation in only three patients in whom gonadotropin results were equivocal without the benefit of biopsy Attempts at induction of ovulation with exogenous gonadotropin failed, and all attempts were dropped when repeat urinary gonadotropin levels were found to be elevated. In the gonadotropin-resistant ovary syndrome, treatment with massive doses of exogenous gonadotropins might appear logical, but the results have been disappointing. Only a few investigators have observed any

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response to the exogenous gonadotropins.17 The only pregnancies following exogenous gonadotropin therapy in patients presumably having the gonadotropinresistant ovary syndrome were reported by Zourlas and Comminos7* and by Zourlas and Mantzavinos.7g Four pregnancies resulted after treatment with human menopausal gonadotropins in dosages below 3,750 IU of FSH per cycle. 7g In these four patients, one set of twins was delivered and hyperstimulation occurred in another patient. The authors classified these patients, along with 26 other patients, as having “primary amenorrhea with normally developed secondary sex characteristics.” The remaining patients were eugonadotropic or hypogonadotropic but had similar ovarian histologic findings. Whether these women, all of Greek origin and representing 1.5% of the authors’ infertility population, are variants of the gonadotropin-resistant ovary syndrome is unknown. Sporadic ovulatory cycles have been reported in women with the gonadotropin-resistant ovary syndrome after wedge resection, dexamethasone, and estrogen replacement therapy.‘jO, ~2 6j, 72 In two cases pregnancies resulted.‘j5’ I2 When one considers the women who became pregnant after a diagnosis of premature follicular depletion, duration of amenorrhea, ovarian biopsy results, and hormonal profiles do not seem very reliable as predictive indicators. Shangold and associatesi reported the case of a 29-year-old woman with a prior history of regular menses who was initially seen for oligomenorrhea of 2 years’ duration following discontinuation of oral contraceptives. Urinary gonadotropin levels were normal at the time. Several attempts at ovulation induction were made, with two ovulatory cycles and no pregnancy. She became amenorrheic, in spite of continued trials with Clomid and human menopausal gonadotropin/human chorionic gonadotropin. Ovarian biopsy revealed an absence of primordial follicles. Six years after her original workup, she was begun on a regimen of estrogen/progestin therapy because of frictional dyspareunia. The serum FSH level was markedly elevated and the serum estrogen concentration was in the low range of normal. Seven months later, pregnancy was diagnosed. She was delivered of a healthy infant at term. Five months post parturn she remained amenorrheic and had again developed frictional dyspareunia. Serum levels of FSH, LH, and estrogens were in the postmenopausal range. Polansky and associates’* reported the case of a 30year-old woman, with a long history of irregular menses, with severe oligomenorrhea after discontinuing oral contraceptives. Gonadotropin levels were elevated, but serum estrogen levels were variable during

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I

800

600 E2$

80

Iw

FSH ti

ml

C-e 40 LH

E2 El

mIlJ ml

D-Q 0

40

CYCLE 2 MiCRONlZED

E2

Fig. 3. The serum concentrations of estrone (E,), EP, LH, and FSH in a woman with premature follicular depletion after Clomid treatment (cycle 1) and an estrogen-primed Clomid treatment cycle are shown. Preceding cycle 2 the patient received 2 mg of micronized El per day for 25 days and progesterone in oil, 50 mg intramuscularly, on the last day of treatment. Day 1 of cycle 2 was 7 days after micronized estradiol was discontinued and the third day of menses. All serum concentrations on days when LH was measured were from pooled serum.

that year. Biopsy revealed an ovary devoid of follicles. One rtronth after a trial of Premarin, she experienced a spontaneous vaginal bleeding and pregnancy was diagnosed 2 months afterward. A majority of patients conceiving after being diagnosed as having premature follicular depletion received estrogen therapy. Because of this, estrogen therapy has been suggested as responsible for resumption of ovulatory function in patients with hypergonadotropic hypogonadism. It is hypothesized that

exogenous estrogens are capable of inducing FSH receptors in the few remaining folkles.*3* 20 Whether the estrogen concentration achieved with replacement therapy is capable of inducing FSH receptors has not been verified.6s Other possible explanations for beneficial effects of estrogen therapy on follicle stimulation would include avoidance of “down regulation” after continuous exposure to high concentrations of gonadotropins and an increase in the biologic/immunologic ratio of endogenous gonadotropins.sO The retrospec-

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tive nature of the pregnancy reports after estrogen therapy, however, leaves many questions concerning its efficacy. Fig. 3 shows the serum levels of FSH, LH, and Ez in a patient with idiopathic follicular depletion possessing a few follicles on ovarian biopsy. Following treatment with clomiphene citrate, FSH fell and LH rose, but E2 remained within the early to middle follicular phase range. The patient was subsequently treated with 2 mg of micronized Ez per day followed by 5 days of clomiphene citrate, 50 mg/day. After discontinuation of the estrogen, serum Ez levels continued to rise and reached values exceeding those found in the normal mensti-ual cycle. Repetition of this treatment failed to yield similar results. We have been unable to confirm that estrogen therapy plays any role in reestablishing follicular sensitivity to the endogenous gonadotropins in hypergonadotropic patients with premature follicular depletion. Regardless, estrogen and progestin therapy is indicated for prevention of metabolic changes resulting from estrogen deficiency. Estrogen replacement therapy has been strongly recommended in all patients with ovarian failure occurring before age 35.81* s2 Estrogen therapy would appear beneficial to prevent osteoporotic changes, atherosclerotic coronary vascular disease, and frictional dyspareunia. Cyclic low-dose estrogen with 10 to 14 days of progestin therapy is recommended.82

Comment For the majority of women in whom an elevated serum FSH concentration has been documented, the chance of future reproduction is minute. One must, therefore, question whether additional diagnostic studies or treatment regimens beyond estrogen and progestin replacement are warranted. At present there are insufficient data to answer this question. Retrospective studies have documented the association of premature

February Am. J. Oket.

1. 1983 Gynecol.

follicular depletion and autoimmune disease, polyglandular failure, and suppressed immunity. Future studies must answer what prognostic value immunologic studies and endocrine challenge tests have before they are advised for patient care. Reports of pregnancies, follicular function, and residual ovarian follicles after a diagnosis of premature follicular depletion challenge our current diagnostic capabilities. They also suggest that attempts at induction of ovulation may be beneficial to some women with this diagnosis. From limited data Rebar and associateslO have recommended weekly determinations of serum Ez concentrations for 1 month and ovarian wedge biopsies to identify hygonadotropic women with residual ovarian follicles.’ While not agreeing with the time sequence for sampling or the need for removing a large portion of ovarian tissue, we do agree that protocols to identify and try to induce ovulation in women with residual ovarian follicles should be considered. We would recommend that two forms of treatment be offered to hypergonadotropic women. After a hypergonadotropic state is confirmed and a karyotype is determined, if indicated, most women should be counseled and placed on a regimen of replacement therapy. Clinical evaluation should be performed at 6-month intervals to assess for any illnesses associated with premature follicular depletion. For women who understand and are willing to participate, an investigation research protocols should be established. It is for this group of women that our classification system requiring ovarian biopsy by means of laparoscopy or laparotomy, karyotype determination, and immune competence testing is proposed. It should not be concluded from this review that hypergonadotropism is necessarily a dead-end diagnosis but rather that further research is warranted. Premature menopause should not be equated with an early physiologic menopause.

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