Chapter 86
XX Gonadal Dysgenesis and Premature Ovarian Failure in 46,XX Individuals
Joe Leigh Simpson
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Joe Leigh Simpson, MD
Ernst W. Bertner Chairman and Professor, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas (Vol 2, Chap 6, Vol 3, Chaps 69, 110, 112; Vol 4, Chap 66; Vol 5, Chaps 75, 79, 80, 83, 84, 85, 86, 87, 90, 95; Vol 6, Chap 37)


Phenotypic females with normal chromosomal complements (46,XX or 46,XY) may have gonadal failure. External appearance may be identical in the two situations, and gonadal findings similarly indistinguishable from 45,X gonadal dysgenesis (Turner syndrome). The general term XX gonadal dysgenesis can be applied to those 46,XX cases. Mosaicism with a coexisting 45,X line is always a possibility, but usually this seems to be excluded. In this chapter the genetic (mendelian) course of ovarian failure in 46,XX women is discussed. A wide spectrum of disorders exists (Table 1). In this chapter premature ovarian failure, sometimes caused by the same factors that cause complete ovarian failure (primary amenorrhea), is also considered. Chapter 5-85 considers ovarian failure caused by abnormalities of the X chromosome (Turner syndrome), and begins with a review of reproductive embryology to which the reader may wish to refer. In Chapter 5-87, 46,XY females, who have complete failure of testicular development and sometimes present with similar appearance, are discussed.


TABLE 1. The Spectrum of XX Gonadal Dysgenesisa

  XX gonadal dysgenesis without somatic anomalies
  XX gonadal dysgenesis with neurosensory deafness (Perrault syndrome)
  XX gonadal dysgenesis with cerebellar ataxia (hetereogeneous)
  XX gonadal dysgenesis in malformation syndrome (
Table 3)
  XX gonadal dysgenesis as one component of pleiotropic mendelian disorders (Table 4)
  FSHR mutations
  LHR mutations
  Blepharophimosis-ptosis-epicanthus (FOXL2)
  Germ cell absence in both sexes (46,XX)

  Without somatic anomalies36,37
  Associated hypertension and deafness38
  Associated alopecia39
  Associated microcephaly and short stature40

  Adrenal and ovarian biosynthetic defects

  17α-hydroxylase (CYP17)
  Aromatase (CYP19)

  Agonadia (46,XX cases)
  Inborn errors of metabolism

  Galactosemia (galactose uridyl-transferase deficiency [GALT])
  Carbohydrate-deficient glycoprotein (Phosphomannomutase deficiency [PMM2])

  Dynamic mutations (triplet repeat)

  Fragile X (FRAXA)
  Myotonic dystrophy (uncommon)

  Ovarian-specific autoimmune
  Polyglandular autoimmune syndrome
  Autosomal trisomies

  Trisomy 13
  Trisomy 18

aIn some conditions, premature ovarian failure is observed as well. FSHR, follicle-stimulating hormone receptor; LSHR, luteinizing hormone receptor.


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XX Gonadal Dysgenesis Without Anomalies

The forms of 46,XX gonadal dysgenesis not associated with somatic anomalies is most often inherited in autosomal recessive fashion. Affected individuals are normal in stature (mean height, 165 cm)1; somatic features of Turner’s stigmata are usually absent. Presence of consanguinity pointed to autosomal recessive inheritance decades ago. Segregation analysis by the author and colleagues revealed the segregation ratio to be 0.16 for female sibs.2 Thus, two thirds of gonadal dysgenesis in 46,XX individuals is genetic. The nongenetic phenocopies could be caused by infection, infarction, infiltrative or autoimmune phenomena (see Chapter 5-88 for further discussion).

Of clinical relevance is the variable expressivity in XX gonadal dysgenesis. In some families one sib has streak gonads, whereas another had primary amenorrhea and extreme ovarian hypoplasia (presence of a few oocytes).1,2,3,4,5,6 If the mutant gene responsible for XX gonadal dysgenesis were capable of variable expression, that gene may be responsible for some sporadic cases of premature ovarian failure (POF).

The mechanism underlying failure of germ-cell persistence in XX gonadal dysgenesis without somatic anomalies is unknown, but there are many candidate genes. Any abnormality of meiosis could be manifested as ovarian failure and infertility in otherwise normal women. Other mechanisms by which mutant genes could act include interference with germ-cell migration, connective tissue abnormalities, or gonadotropin receptor abnormalities.

Identifying the specific autosomal genes responsible for the various forms of XX gonadal dysgenesis has been difficult. In many monogenic disorders efforts toward positional cloning are facilitated by the fortuitous family in which an autosomal translocation cosegregates with the disorder. Sporadic cases of XX gonadal dysgenesis have long been associated with reciprocal autosomal translocations, but there seems to be little reproducibility among autosomes involved. Genome-wide sib-pair analysis using polymorphic DNA markers (dinucleotide repeats; single nucleotide polymorphism) should theoretically identify chromosomal region(s) worthy of sequencing. Indeed, this method was used successfully in Finland to elucidate the form of XX gonadal dysgenesis caused by follicle-stimulating hormone receptor (FSHR) mutation, which we shall discuss below.5,7 Construction of cDNA libraries of ovarian specific genes represent a more omnibus approach, combined with use of gene knockout technology in the mouse and sequencing of candidate genes in the human. Many mouse genes are of potential relevance (Table 2), and perturbations in their human homologues can be sought. Many of these genes may only manifest as ovarian failure, in contrast to predictions that other organ systems would also be disturbed. An example is bone morphogenetic protein (bmp). The conclusion is that ovarian meiosis is easily perturbed, secondarily leading to germ-cell failure.


TABLE 2. Selected Mouse Models of Ovarian Failure

Mutant Mouse/Transgene

Human Locus


Mouse Phenotype

Prenatal ovarian failure defects




Zinc finger X (zfx) knockout


Transcription factor

Reduced number of oocytes, infertility, short stature [Luoh and colleagues98]

Germ-cell deficient (gcd) unknown


Unknown gene, generated by transgene insertion

Lack of germ cells in early as day 11.5 of embryonic development [Pellas and colleagues99]

White spotting (W)


Tyrosine kinase receptor

Reduced pigmentation, anemia, lack of germ cells [Manové and colleagues100]

Steel (Sl)


Mast cell growth factor

Reduced pigmentation, anemia, lack of germ cells [Matsui and colleagues101]

Steroidogenic Factor 1 (SF-1) knockout


Nuclear receptor factor

Ovarian agenesis, XY sex reversal, adrenal agenesis [Luo and colleagues102]

mutS (E. coli) homolog 5 (MSH 5)


DNA mismatch repair

Absence of ovarian structure, normal oviducts and uteri [Edelmann and colleagues103]

Beta cell leukemia/lymphoma 2(Bcl-2) knockout


Cell death repressor protein

Accelerated atresia of primordial follicles [Ratts and colleagues104]

Factor in germline α (Figα)


Transcription factor

Females lack primordial follicles, males are normal [Soyal and colleagues105]

Postnatal ovarian failure defects




Growth differentiation factor 9 (GDF9)


Oocyte secreted growth factor

Block in prenatal follicle development, infertility [Dong and colleagues106]

Follicle-stimulating hormone β


Glycoprotein hormone

Female infertility, block of folliculogenesis before antral stage subunit ββ knockout (FSHβ) [Kumar and colleagues107]

FSH receptor (FSHR) knockout


Hormone receptor

Female infertility, block in folliculogenesis before antral stage [Dierich and colleagues108]

Estrogen receptor α (Erα) knockout


Hormone receptor

Absent corpora lutea, arrest of preovulatory follicle maturation [Lubahn and colleagues109]

Connexin 37 knockout


Gap junction

Lack of Graafian follicles, failure to ovulate [Simon and colleagues110]

mutL (E. coli) homologue 1 (MLH1)


DNA repair enzyme

Failure to complete meiosis II, normal estrous cycle [Edelmann and colleagues111]

Zona matrix protein 3 (mZP3) knockout


Zona pellucida

Infertility, oocytes lack zona pellucida [Rankin and colleagues112]

Nerve growth factor-induced gene NGFI- A knockout


Transcription factor

Lack of corpora lutea, suppressed luteinizing hormone levels [Topilko and colleagues113]

(From Simpson JL, Rajkovic A: Ovarian differentiation and gonadal failure. Am J Med Genet 89:186, 1999.)


Perrault Syndrome (XX Gonadal Dysgenesis with Neurosensory Deafness)

XX gonadal dysgenesis associated with neurosensory deafness is called Perrault syndrome.8 Perrault syndrome is inherited in autosomal recessive fashion.1,9,10,11,12 Endocrine features seem identical to XX gonadal dysgenesis without deafness.

XX Gonadal Dysgenesis Caused by Follicle Stimulating Hormone Receptor Mutation (Val566 A1a)

This disorder is found predominantly in Finland, where Aittomaki and colleagues5,7 searched hospitals and cytogenetic laboratories throughout the country to identify 75 subjects having the XX gonadal dysgenesis phenotype. Diagnostic criteria consists of 46,XX women with primary or secondary amenorrhea whose serum FSH was 40 MIU/mL or more. The 75 included 57 sporadic cases and 18 cases having an affected relative (7 different families). Most resided in north central Finland, a more sparsely populated part of the country. Prevalence was 1 per 8300 liveborn Finnish females. This relatively high incidence is attributed to a founder effect. The segregation ratio of 0.23 for female sibs was almost identical with theoretical expectations for autosomal recessive inheritance. This is consistent with a high consanguinity rate (12%).

Sib pair analysis using polymorphic DNA markers first localized the gene to chromosome 2p, a region previously known to contain the genes for both the FSHR and the luteinizing hormone receptor (LHR). One specific mutation (Val to Ala) in exon 7 of the FSHR gene was found in 6 families5,7 (Fig. 1). This cytosine-thymidine transition (called C566T) was later found in an additional 6 families.7,13

Fig. 1. Schematic presentation of the follicle stimulating hormone receptor (FSHR) and gene structure. The locations of the three known inactivating mutations are designated with black squares. Exons are separated with a short line. EC, extracellular domain; TM, transmembrane domain; IC, intracellular domain.(Aittomaki K: FSH receptor defects and reproduction. In: Kempers RD, Cohen J, Haney AF, et al (eds): Fertility and Reproductive Medicine. P. 762. New York, Elsevier Science, 1998.)

Not all Finnish XX gonadal dysgenesis cases show the C566T mutation. Thus, the C566T-negative cases in Finland could represent the previously discussed condition XX gonadal dysgenesis with no somatic anomalies. Indeed, the C566T mutation is only rarely being detected in women with 46,XX ovarian failure who reside outside Finland. In the United States, Layman and colleagues14 failed to find a mutation in FSHR gene in 35 46,XX women having hypergonadotopic hypogonadism (15 with primary amenorrhea; 20 with secondary amenorrhea). Negative findings were reported in 46,XX POF or primary amenorrhea cases from Germany,15 Brazil,16 and Mexico.17 The last report analyzed all exons of FSHR. Liu and colleagues18 found no FSHR abnormalities in one multigenerational U.S. POF family, four sporadic POF cases and two other hypergonadotopic hypogonadism cases.

Aittomaki and colleagues13 compared the phenotype of Finnish C566T XX gonadal dysgenesis (C566T) with non-C566T XX gonadal dysgenesis. The former were more likely to have ovarian follicles by ultrasound. C566T XX gonadal dysgenesis thus showed at least some of the features gynecologists have long predicted for a gonadotropin resistance disorder (so-called Savage syndrome). In general, however, the phenotype found by Aittomaki5 was unexpected, bilateral streak gonads being found. FSHR (knockout) mice similarly show failure of oogenesis; thus, the necessity of FSH for progression of oogenesis is clear.19 Interestingly, FSH is less pivotal for spermatogenesis.20

Inactivating Luteinizing Hormone Receptor Mutation (46,XX)

Another trophic hormone receptor gene, the perturbation of which causes XX gonadal dysgenesis, is the LHR. The gene is 75 kd in length and consists of 17 exons. Located on 2p near FSHR, the first 10 exons in LHR are extracellular; the last 6 are intracellular, and the 11th, transmembrane. LHR mutations have been reported predominately in 46,XY individuals, where the phenotype may extend to complete LH resistance and XY gender reversal (female). 46,XX cases are more rare than 46,XY cases, and have occurred only in sibships in which an affected 46,XY male had Leydig cell hypoplasia (XY gender reversal).

46,XX women with LHR mutations show oligomenorrhea or, less often, primary amenorrhea. Ovulation does not occur. Gametogenesis proceeds until the preovulatory stage, but not beyond. This is consistent with findings in the mouse knockout model.

Mutations in LHR are molecularly heterogeneous. Most mutations have been found in the transmembrane domain (exon). Latronico and colleagues21 reported primary amenorrhea in a 22-year-old woman whose family also included three affected males (46,XY), like the 46,XX sib homozygous for a nonsense mutation at codon 554 (Arg554ter). The resulting stop codon produced a truncated protein. The affected 46,XX female showed breast development but only a single episode of menstrual bleeding at age 20 years; LH was 37 mIU/mL, FSH 9 mIU/mL. The mutation reduced signal transduction activity of the LHR gene.

Toledo and colleagues22 studied the 46,XX female sib of two 46,XY affected males reported by Cramer and colleagues.23 The sister showed elevated gonadotropins but anatomically normal ovaries. The mutation was Ala593Pro. Two sisters reported by Laue and colleagues24 had the nonsense mutation cys545ter in exon 11; LHR function was lost. The father but not the mother had the mutation. The authors found a dominant negative effect, but more likely the mutant allele transmitted from the probably heterozygous mother has simply not yet been detected.

Cerebellar Ataxia and XX Gonadal Dysgenesis

XX gonadal dysgenesis can be found in association with a heterogeneous group of cerebellar ataxias. The hereditary ataxias are confusing nosologically, principally because of ill-defined diagnostic criteria and lack of direct access to the cerebellum. Forms of ataxia characterized by hypogonadotrophic hypogonadism also exist, but these are not considered here.

The association between hypergonadotrophic hypogonadism and ataxia was first reported by Skre and colleagues.25 In one family, a 16-year old girl was affected, whereas in the other family there were three affected sisters. In the sporadic case and in one of the three sibs, ataxia was observed shortly after birth; in the two other sibs, age of onset occurred later in childhood. Cataracts were present in all individuals described by Skre and colleagues.25

Hypergonadotropic hypogonadism and ataxia was subsequently reported by De Michele and colleagues,26 Linssen and colleagues,27 Gottschalk and colleagues,28 Fryns and colleagues,29 Nishi and colleagues,12 and Amor and colleagues.30 In these various reports the clinical features of ataxia have varied. Findings similar to those of Skre and colleagues25 were reported by De Michele and colleagues,26 Nishi and colleagues,12 and Amor and colleagues30; ataxia was usually not progressive. Mitochondrial enzymopothy was evident in one case reported by De Michele and colleagues,26 but in no other cases were mitochondrial studies conducted. Only Skre and colleagues25 observed cataracts and only Linssen and colleagues27 observed amelogenesis. Neurosensory deafness was reported by Amor and colleagues30 Mental retardation is likewise variable.30

In conclusion, a single mutant gene is unlikely to explain every single case of XX gonadal dysgenesis and cerebella ataxia. However, not every family need to be unique.

XX Gonadal Dysgenesis and Multiple Malformation Syndromes

Several other pleiotropic genes cause XX gonadal dysgenesis and various somatic features. All are rare and in perhaps even unique to a specific family. Table 3 lists these syndromes: XX gonadal dysgenesis, microcephaly, and arachnodactyly31; XX gonadal dysgenesis, cardiomyopathy, blepharoptosis, and broad nasal bridge30,32; XX gonadal dysgenesis and epibulbar dermoid33; XX gonadal dysgenesis, short stature and metabolic acidosis.34 Assuming mendelian etiology, these disorders are presumably autosomal recessive. However, subtle chromosomal rearrangements cannot be excluded.


TABLE 3. Malformation Syndromes with 46,XX Gonadal Dysgenesis

Somatic Features



Cerebellar ataxia, sensori-neural deafness, other somatic features

Amor and colleagues30; Skre and colleagues25

Autosomal recessive, heterogeneous

Microcephaly, arachnodactyly

Maximilian and colleagues31

Autosomal recessive

Epibulbar dermoids

Quayle and Copeland33

Autosomal recessive

Short stature and metabolic acidosis

Pober and colleagues34; Hisama and colleagues114

Autosomal recessive


Zlotogora and colleagues84; Crisponi and colleagues89

Autosomal dominant (FOXL2)

Renal parenchymal disease, ovarian failure (46,XX Frasier syndrome) Wilms tumor and genital ambiguity (Denys-Drash syndrome) different perturbations involving same gene (WT1).

Bailey and colleagues35 (Frasier syndrome)

Autosomal dominant (WT1)

Dilated cardiomyopathy, mental retardation, bleparoptosis (Malouf syndrome)

Malouf and colleagues32; Narahara and colleagues115

Autosomal recessive


In all these syndromes, an underlying biologic question is whether the ostensibly pleiotropic gene(s) causes both somatic anomalies and ovarian failure? Alternatively, could the somatic and gonadal phenotypes merely reflect closely linked genes, that is, a contiguous gene syndrome? Irrespective, do these purported genes play roles in normal ovarian differentiation, or does their perturbation merely cause ovarian failure secondary to generalized somatic disturbance?

Pleiotropic Mendelian Disorders Showing Ovarian Failure

Primary ovarian failure is observed frequently in well-established and not necessarily uncommon in mendelian disorders. All are characterized by distinct somatic features (Table 4). Pleiotrophy for these mutant genes allows clear distinction from disorders previously discussed.


TABLE 4. Autosomal Recessive Disorders the Phenotype of Which is Predominately Somatic but in Which Ovarian Failure is also Observed


Somatic Features

Ovarian Anomalies



Cerebella ataxia, multiple telangiectasias (eyes, ears, flexa surface of extremities), immunodeficiency, chromosomal breakage, malignancy, x-ray hypersensitivity

“Complete absence of ovaries”, “absence of primary follicles” [Zadik and colleagues16; Waldmann and colleagues116]


Carbohydrate-deficient glycoprotein syndrome, type 1 (phosphomannonutase deficiency) [Matthijs and colleagues48]

Neurologic abnormalities (e.g., unscheduled eye movements), ataxia, hypotonial/hyporeflexia strokes, joint cartractures

Ovarian failure (hypogonadism) [Kristiansson and colleagues50]

Autosomal recessive

Cockayne Syndrome [Nance and Berry117]

Dwarfism, microcephaly, mental retardation, pigmentary retinopathy and photosensitivity, premature senility. Sensitivity to ultraviolet light

Ovarian atrophy and fibrosis [Sugarman and colleagues118]

Autosomal recessive

Galactosemia (galactose-l-phosphate uridyl transferase deficiency) (GALT)

Hepatic failure with cirrhosis, renal failure, cataracts, cardiac failure

Ovarian failure with streak gonads [Kaufman and colleagues41; Waggoner and colleagues42; Levey and colleagues43]

Autosomal recessive

Martsolf Syndrome [Martsolf and colleagues119]

Short stature, microbrachycephaly, cataracts, abnormal facies with relative prognathism due to maxillary hypoplasia

“primary hypogonadism” [Harbord and colleagues120] [Hennekam and colleagues121]

Autosomal recessive

Nijmegen syndrome [Weemaes and colleagues122]

Chromosomal instability, immunodeficiency, hypersensity to ionizing radiation, malignancy

Ovarian failure (primary) [Conley and colleagues123; Chrzanowska and colleagues124]

Autosomal recessive

Rothmund-Thompson syndrome [Hall and colleagues125]

Skin abnormalities (telangiectasia, erythrema irregular pigmentation), short statue, cataracts, sparse hair, small hands and feet, mental retardation, osteosarcoma

Ovarian failure (primary hypogonadism or delayed puberty) [Starr and colleagues126]

Autosomal recessive

Werner syndrome [Goto and colleagues127]

Short stature, premature senility, skin changes (scleroderma)

Ovarian failure [Goto and colleagues127]

Autosomal recessive


Of special note is Denys-Drash syndrome and Frasier syndrome, which are caused by mutations in WT-1 (Wilms’ tumor-1), a gene located on 11p. WT-1 mutations can cause either 46,XY gender reversal or 46,XY genital ambiguity. One 46,XX individual with Frasier syndrome has been reported.35 This woman manifested not only the renal parenchymal disease characteristic of Frasier syndrome, but also primary amenorrhea and ovarian failure. Gonadal failure in 46,XX Frasier syndrome could easily pass unappreciated if the primary amenorrhea is assumed to occur secondary to azotemia.

Germ-Cell Failure in Male (46,XY) and Female (46,XX) Sibs

In several sibships, male and female sibs have shown germinal cell failure. Affected 46,XX females showed streak gonads, whereas 46,XY affected males showed germ-cell aplasia (Sertoli-cell–only syndrome). In two families, parents were consanguineous, and in each there were no somatic anomalies.36,37 In three other families (see Table 1), characteristic somatic anomalies suggested distinct entities. Hamet and colleagues38 observed germ-cell failure, hypertension, and deafness; Al-Awadi and colleagues39 found germ-cell failure and alopecia; Mikati and colleagues40 reported germ-cell failure, microcephaly and short stature.

In each of these families a single autosomal gene is presumed to affect germ cell development deleteriously in both sexes. This gene(s) could act either at a specific site common to early germ cell development or exert its effect through meiotic breakdown. Elucidating such genes could help explain normal germ cell development. Indeed, a variety of attractive candidate genes exist in mouse and Drosphila (see Table 2). An example is gcd, a mouse mutant in which germ cells are deficient in both males and females.


Galactosemia is caused by deficiency of galactose 1-phosphate uridyl transferase (GALT). The gene is located on 9p. Long-recognized features included renal, hepatic, and ocular defects. Kaufman and colleagues41 reported POF in 12 of 18 galactosemic women, and Waggoner and colleagues42 observed ovarian failure in 8 of 47 females. Pathogenesis presumed to involve galactose toxicity during infancy or childhood; elevated fetal levels of toxic metabolites should be cleared rapidly in utero by maternal enzymes. Consistent with this hypothesis, a neonate with galactosemia showed normal ovarian histology.43

Given the clinical severity of galactosemia and the absolute necessity for dietary treatment during childhood to prevent mental retardation, it seems highly unlikely that previously undiagnosed galactosemia would prove to be the cause of ovarian failure in women presenting solely with primary amenorrhea or POF. Of greater relevance to gynecology, therefore, was the report in 1989 by Cramer and colleagues44 that GALT heterozygotes were at increased risk for POF.44 However, the same author later failed to observe GALT abnormalities in another sample of women with early menopause,23 and Kaufman and colleagues45 likewise failed to confirm the observation. Moreover, not all homozygotes for human galactosemia are abnormal, nor are transgenic mice in which GALT is inactivated.46

Carbohydrate-Deficient Glycoprotein Intrauterine Contraceptives (Cdg) [Phosphomannomutase Deficiency [PMM2])

In type 1 carbohydrate-deficient-glycoprotein (CDG) deficiency, mannose-6-phosphate cannot be converted to mannose-1-phosphate. Thus, the lipid-linked mannose-containing oligosaccharides needed for secretory glycoproteins are lacking. The CDG gene is located on 16p13. The molecular pathogenesis is usually a missense mutation.47

The wide spectrum of neurologic abnormalities includes hypotonia, hyperreflexia, unprovoked eye movements, ataxia, joint contractions, epilepsy, and stroke-like episodes.48 Subcutaneous fat deposits, hepatomegaly, cardiomyopathy, pericardial effusion, and factor XI (clotting) deficiency develop.

Of interest here is that ovarian failure occurs; the ovaries are devoid of follicular activity.49,50

Deficiency of 17α-Hydroxylase/17,20-Desmolase (Lyase) Deficiency (Cyp17)

Sex steroid synthesis requires intact adrenal and gonadal biosynthetic pathways. Various gene products (enzymes) are necessary to convert cholesterol to testosterone and androstenedione and, hence, estrogens. The various enzyme blocks have varying but predictable consequences, depending on their site in the biosynthetic pathway (Fig. 2). The most common adrenal biosynthetic problem is involving deficiency of 21- or 11β-hydroxylase, either of which causes pseudohermaphroditism. These disorders cause genital ambiguity because of virilization, but need not be considered in the differential diagnosis of XX gonadal dysgenesis.

Fig. 2. Pivotal adrenal and gonadal biosynthetic pathways. Letters designate enzymes or activities required for the appropriate conversions. A, 20α-hydroxylase, and 20,22-desmolase; B, 3β-ol-dehydrogenase; C, 17α-hydroxylase; D, 17,20-desmolase; E, 17-ketosteroid reductase; F, 21-hydroxylase; G, 11β-hydroxylase; H, aromatase. In addition to these enzymes, steroid acute regulatory protein (StAR), designated I, is responsible for transporting cholesterol to the site of steroid biosynthesis. Finally, 17α-hydroxylase (C) and 17,20-desmolase (D) activities are actually governed by a single gene.(Simpson JL, Elias S: Genetics In Obstetrics and Gynecology, p 270. 3rd ed. Philadelphia, WB Saunders, 2003.)

If the cytochrome P450 enzyme 17α-hydroxylase/17-20-lyase is deficient, pregnenolone cannot be converted to 17α-hydroxy-pregnenolone. If the enzyme defect were complete, cortisol, androstenedione, testosterone, and estrogens could not be synthesized; however, 11-deoxycorticosterone and corticosterone could. With compensatory increase in adrenocorticotropic hormone (ACTH secretion), 11-deoxycorticosterone and corticosterone increase to result in hypernatremia, hypokalemia, and hypervolemia. Hypertension occurs. Aldosterone is decreased, presumably because hypervolemia suppresses the renin-angiotensin system.

Females (46,XX) with 17α-hydroxylase deficiency have normal external genitalia, but at puberty fail to undergo normal secondary sexual development (primary amenorrhea). Affected males (46,XY) usually have genital ambiguity (male pseudohermaphroditism) because partial expression of the gene produced some androgens. Affected females are ordinarily encountered in differential diagnosis of XX gonadal dysgenesis. Hypertension is the major distinguishing clue. Oocytes appear incapable of spontaneously exceeding a diameter greater than 2.5 mm,51 but ovaries nonetheless respond to exogenous gonadotropins.52

17α-hydroxylase deficiency is inherited in autosomal recessive fashion. The gene (CYP17) is located on 10q24-25, and the gene product is a cytochrome P450 enzyme. More than 20 different mutations have been identified in CYP17, scattered among the 8 exons. Mutations include missense mutations, duplications, deletions, and premature protein truncation.53 Most mutations have been observed in only a single family, yet another example of molecular hetereogeneity. An exception exists in Mennonites of Dutch origin, where a 4-base duplication in exon 8 accounts for most cases.54 This founder mutation originated in Friesland.

This single gene (and enzyme) is responsible for both 17α-hydroxylase and 17,20-desmolase (lyase) actions (see Fig. 2). A few patients having deficiency of both 17α-hydroxylase and 17,20 lyase activities have been analyzed, with mutations different from those only showing deficient 17α-hydroxylase activity have been found.55,56 Transfection experiments show that only 5% of 17α-hydroxylase activity is sufficient for the estrogen production necessary for normal secondary sexual characteristics in a 46,XX individual; however, 25% of enzyme activity is necessary to virilize external genitalia in males.53,55 Targeted mutagenesis in the rat gene indicates that mutations closer to the 5′ end are more deleterious.

Aromatase Mutations (Cyp19)

Conversion of androgens (Δ4-androstenedione) to estrogens (estrone) requires cytochrome P-450 aromatase, an enzyme product of a 40-kb gene located on chromosome 15q21.1.57 Deficiency of the aromatase enzyme in 46,XX individuals is most often associated with clitoral hypertrophy or genital ambiguity, but 46,XX aromatase deficiency may present as primary amenorrhea in phenotypic females.

Ito and colleagues58 reported aromatase mutation (CYP19) in an 18-year-old 46,XX Japanese woman having primary amenorrhea and cystic ovaries. Compound heterozygosity, existed for two point mutations in exon 10. The mutant protein had no activity. Conte and colleagues59 reported aromatase deficiency in a 46,XX woman presenting with primary amenorrhea, elevated gonadatropins, and ovarian cysts. Compound heterozygositly also existed for two mutations in exon 10. One mutation was ′ C1303T (cysteine rather than arginine); the other was ′ G1310A (tyrosine rather than cysteine).

Mullis and colleagues60 reported clitoral enlargement at puberty. No breast development occurred. FSH was elevated; estrone and estradiol were decreased. Multiple ovarian follicular cysts were evident. Hormonal (estrogen and progesterone) therapy produced a growth spurt, breast development, menarche, and decreased numbers of follicular cysts. Compound heterozygosity existed in CYP19.

46,XX Agonadia

Agonadia usually occurs in 46,XY individuals but, rare 46,XX cases exist. As in 46,XY agonadia, gonads are absent, in 46,XX agonadia. This contrasts with persistence in the form of streaks (gonadal dysgenesis). External genitalia are abnormal but female-like; no more than rudimentary Müllerian or wolffian derivatives are present. External genitalia usually consist of a phallus about the size of a clitoris, underdeveloped labia majora, and nearly complete fusion of labioscrotal folds. Thus, external genitalia are nearly or somewhat female in appearance. In approximately one half of cases, somatic anomalies coexist: craniofacial anomalies, vertebral anomalies, and mental retardation.

Agonadia must be considered in the differential diagnosis of 46,XX primary amenorrhea. The 46,XX agonadia cases reported by Duck,61 and Levinson62 were sporadic. Mendonca and colleagues63 reported agonadia without somatic anomalies in phenotypic sibs having unlike chromosomal complements (46,XY and 46,XX). Kennerknecht and colleagues64 reported agonadism, hypoplasia of the pulmonary artery and lung, and dextrocardia in XX and XY sibs.

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Premature ovarian failure can result from nongenetic causes as well as several different genetic causes (Table 5). Genetic or familial POF can be stratified into these four general etiologies: (1) autosomal rearrangements, (2) X-chromosomal abnormalities, (3) autosomal recessive genes (sometimes the same genes resulting in the various forms of XX gonadal dysgenesis; see above); (4) autosomal chromosomal rearrangements, and (5) autosomal dominant genes including whose action may or may not be restricted to POF. In addition, the possibility exists that some cases of POF merely represent the lower end of the normal population with respect to ovarian number and function (i.e., early but normally executed menopause). We shall first consider this concept.


TABLE 5. Genetic Causes of Premature Ovarian Failure

  Premature ovarian failure as normal continuous variation: heritable early menopause
  Autosomal chromosomal rearrangements
  X-chromosomal abnormalities
  Autosomal recessive premature ovarian failure (
Table 1)
  Autosomal dominant premature ovarian failure (Table 6)
  Blepharophimosis-ptosis-epicanthus (FOXL2) (Table 7)
  Fragile X syndrome and expansion of triplet nucleotide repeats (CGG) (Table 8)
  Myotonic dystrophy and expansion of triplet repeats (CTG)
  Premature ovarian failure and polyglandular autoimmune syndrome
  Premature ovarian failure associated with anti-ovarian antibodies or oophorities (genetic basis?)


Premature Ovarian Failure as Normal Continuations Variation: Heritabile Early Menopause

Oocyte number (reservoir) could be low in some women simple on statistical (stochastic) grounds. Normal distribution exists for all common anatomic traits (e.g., height), and this principle must apply to oocyte number and reservoir at birth. Different rodent strains show characteristic breeding duration, implying genetic control over either the rate of oocyte depletion or the number of oocytes initially present. That a normal distribution of germ cell number exists in ostensibly normal females is thus well established in animals, but difficulty to prove in humans. Nonetheless, some ostensibly normal (menstruating) women should have decreased oocyte reservoir or increased oocyte attrition on a genetic basis, analogous to animal models.

In humans, a genetic basis for the above can also be presumed by analogy to the heritability of age at human menopause, a characteristic that clearly shows familiar tendencies. However, determining heritability of age of menopause in humans is complicated because of iatrogenic factors (e.g, hysterectomy) and other confounders (e.g., presence of leiomyomata). Cramer and colleagues23 took these confounders into account in a case-control study of 10,606 U.S. women. Women with an early menopause (40 to 45 years) were age-matched with controls who were either still menstruating or who had experienced menopause after age 46. Of 129 early menopause cases, 37.5% had a similarly affected mother, sister, aunt, or grandmother. Only 9% of controls had such a relative (odds ratio after adjustment 6.1, 95% confidence interval [CI] 3.9 to 9.4). As predicted on the basis of polygenic inheritance, the odds ratio was greatest (9.1) for sisters and greater when menopause occurred prior to 40 years. Incidentally, frequency of galactose 1-phosphate uridyltransferase (GALT) variants (N314D or Q188R) did not deviate from that expected in early menopause cases, in contrast to earlier studies by the same authors.44 The results of Cramer and colleagues23 were confirmed by Torgerson and colleagues,65 who studied women undergoing menopause during the 5-year centile ages 45 to 49 years. The likelihood was increased that menopause would occur in a similar 5-year centile in their daughters.

Twin studies have confirmed heritability of age at menopause.66 Snieder and colleagues67 studied 275 monozygotic (MZ) and 353 dizygotic (DZ) U.K. twin pairs. For age at menopause, correlation (r) was 0.58 for MZ and 0.39 DZ twins; heritability (h2) was calculated to be 63%. The study of Treloar and colleagues68 involved 466 MZ and 262 DZ Australian twin pairs. For age at menopause the correlation (r) was 0.49 to 0.57 for MZ and 0.31 to 0.33 for DZ twin pairs. Differences between MZ and DZ held when iatrogenic causes of menopause was taken into account.

Autosomal Chromosomal Rearrangements

Autosomal chromosomal rearrangements can also lead to premature ovarian failure with many different reciprocal translocations involved. The underlying mechanism is presumably meiotic breakdown. About 2% of azoospermic or oligospermic men who present for intracytoplamic sperm injection (ICSI) but are otherwise clinically normal show balanced autosomal translocations.69,70

Approximately 2% of their ostensibly normal female partners also show balanced translocations. A relation thus also exists between balanced translocations and infertility in women, but lack of a readily assayed end point to pinpoint infertility makes studies more difficult in females than in men. The frequency in infertile women having normal male partners has not been crisply defined because of pronounced biases of ascertainment in almost all series. However, the prevalence is surely at least 2% and probably higher. The same translocation almost certainly predisposes to POF or early menopause.

Detecting individuals with a chromosomal rearrangement is important not only as an explanation for their offspring are at risk far unbalanced chromosomal abnormalities.

Autosomal Dominant Premature Ovarian Failure

Autosomal dominant familial tendencies per se have long been recognized in cytogenetically normal women with POF who have no other clinical abnormalities. Thus, discussion here excludes X-abnormalities [del(Xp) and (Xq)] and the syndrome blepharophimosis-ptosis-epicanthus as a result of FOXL2 perturbations. Other samples of women with POF report high frequencies of associated abnormalities, such as Kim and colleagues71; 22 of 119 women with POF (18.5%) were hypothyroid, and 3 had Addison’s disease. Although this seems atypical, for many years it was widely assumed that familial tendencies in POF merely reflected autoimmune phenomena. In women with POF, antibodies against adrenal,72,73,74 thyroid,75 and pancreas73 may be detected76; however, autoimmune factors are not always or even often observed. Familial tendencies in the absence of autoimmune findings are more common. This was observed decades ago. Coulam and colleagues77 reported POF in sibs who had an affected mother and aunt. Affected individuals in more than one generation were reported by Starup and Sele,78 Austin and colleagues,79 and Mattison and colleagues.80 In none of these families were autoimmune phenomena observed.

In Italy, Testa and colleagues81 and Vegetti and colleagues82 are systematically studying women first with POF (menopause at younger than 40 years of age) recruited from a large northern Italian population. After excluding 10 cases with known etiologies (5 chromosomal, 3 prior ovarian surgery, 1 prior chemotherapy, 1 galactosemia), 71 probands remained. Of the 71, 22 (31%) had other affected relatives (Table 6). An expanded sample of 130 cases found 28.5% familial cases.83 Patterns of inheritance observed were consistent with autosomal or X-linked dominant inheritance; transmission through both maternal and paternal lineage was observed. Among 30 other women experiencing early menopause (40 to 50 years) half showed other affected relatives. There further is evidence that POF (younger than 40 years) and early menopause (menopause at 40 to 50 years) represent the same phenomena. The two different phenotypes have been observed within a single kindred, transmission through either a paternal or maternal relative.


TABLE 6. Frequency of Heritable Premature Ovarian Failure in an Italian Referral Sample

Known etiology (N = 10)

Abnormal chromosomal


Prior ovarian surgery


Prior chemotherapy




Idiopathic (N = 71)


No family history


Family history

22 (31%)



Data of Vegetti and colleagues.


Pathogenic mechanisms for autosomal dominant premature ovarian failure include decreased number of primordial follicles or human homologous of mouse cited in Table 2. Nongenetic etiologies (phenocopies) might include infiltrative disease (e.g., sarcoidosis), toxins, or autoimmune phenomenon. Environmental causes are unlikely to explain intergenerational familial aggregates.

Blepharophimosis-Ptosis-Epicanthus (FOX L2)

Blepharophimosis-ptosis-epicanthus (BPE) is an autosomal dominant multiple malformation syndrome long known to be associated with ovarian failure. Usually POF exists, not complete ovarian failure84,85. In one unusual case, Fraser and colleagues86 reported that the ovaries of an affected individual were unresponsive to gonadatropins.

Sib-pair analysis using polymorphic DNA variants87 localized the gene to chromosome 3 (3q22→24), a region that contains no obvious candidate gene.88 Positional cloning revealed mutation in the one exam, winged helix/forkhead transcription factor gene (FOXL2), yielding a truncated protein89 in each of four cases (Table 7). This indicates the mechanism of gene action is haplo-insufficiency. Mutations observed included three stop codons (X) and a 17–base pair duplication causing a frameshift and, hence, truncated gene product. Postulated FOXL2 gene function includes inhibition of proapoptotic genes such as tumor necrosis factor (TNF)-α, thus, on sustaining follicle viability.


TABLE 7. FOXL2 Mutations in Blepharophimosis-Ptosis Epicanthus Syndrome (BPES, type 1)



Amino Acid











737T→A; 738C→A


Data of Crisponi and colleagues.


The gene is expressed in mesenchyma of mouse eyelids and in adult ovarian follides, consistent with phenotype observed in the mutation of the human homologue BPE.

Fragile X Syndrome and Expansion of Triplet Nucleotide Repeats (CGG)

A molecular mechanism seemingly relevant to ovarian development is expansion of triplet nucleotide repeats. The prototype is the fragile X syndrome, caused by mutation of the FMRI gene on Xq27. Fragile refers to a tendency toward chromosomal breakage when affected cells are cultured in folic acid-deficient media. Various fragile sites exist in humans, but only FRAXA and FRAXE in particular are relevant to the present discussion.

In FRAXA, males show mental retardation, characteristic facial features, and large testes. The molecular basis involves repetition of the triplet repeat CGG (CGG)n 230 times or more (Fig. 3). Ordinarily, the normal number of repeats in males is only 6 to 50. When heterozygous females show 50 to 200 repeats, a permutation is said to be present. During female (but not male) meiosis the number of triplet repeats may increase (expand). A woman with a FRAXA premutation may have an affected son if the number of CGG repeats on the X transmitted to her offspring were to expand during meiosis to more than 230 repeats; her son would then inherit that expanded X and, hence, be affected. These molecular changes are readily seen by straightforward molecular studies (Fig. 4). Females may also be affected if expansion occurs, but show a less severe phenotype than males.

Fig. 3. Diagram of the FMR1 gene and the first exon in normal, premutation, and full mutation alleles. The oval immediately to the left of the start site of transcription represents the promoter region of the FMR1 gene. The open symbol represents active transcription, and the black symbol, silenced transcription. The vertical lines indicate CGG trinucleotides upstream of the methionine codon (AUG) at the translocational start site.(Warren ST, Nelson DL: Advances in molecular analysis of fragile X syndrome. JAMA 271:536, 1994.)

Fig. 4. Southern blot using EcoR1 and Eagl digestion, probed with StB12.3, using extended electrophoresis to illustrate several subtle specimen types. (1) Normal female. (2) Full mutation male. Note the combination of a predominant band with a diffuse smear. (3) Female with 28 and 52 repeats, with the smaller allele predominantly active. (4) Female with 26 and 52 repeats, with the larger allele predominately active. (5) Female with 18 and approximately 80 repeats, with equal X-inactivation. (6) Normal male. (7) Normal male, underloaded and smiling because of DNA degradation. (The apparent line between lane 6 and 7 is a photographic artifact.) (8) Normal female. (9) Normal male. (10) Normal male. (11) Affected male, underloaded and diffuse). (12) Premutation male. (13) Female with 20 and 70 repeats, with the smaller allele virtually exclusively active. The only evidence of abnormality is the slow migration of the 5.2-kb band. (14) Female with 27 and 42 repeats, with the larger allele somewhat more active. (15 to 17) Unremarkable normal females and males. Figure provided by Genetics and IVF Institute.(From Maddalena A, et al: Genetics in Medicine, 2001).

Females with the FRAXA premutation may show POF. Schwartz and colleagues90 reported that fragile X carrier females more often showed oligomenorrhea than noncarrier female relatives (38% versus 6%). Murray and colleagues91 analyzed 1268 controls, 50 familial POF cases, and 244 sporadic POF cases. Of familial cases, 16% showed FRAXA premutation; among sporadic cases, only 1.6% showed POF (Table 8). In the same sample POF was not increased in FRAXE. An international collaborative survey92 of 395 premutation carriers revealed 63 (16%) underwent menopause under 40 years of age; only 0.4% of controls did. Surprisingly, frequency of POF was not increased in 128 FRAXA cases having a full mutation. Consistent with the above are observations that heterozygous FRAXA women respond poorly to ovulation-inducing agents, producing fewer oocytes and fewer embryos in assisted reproductive technologies (ART).93


TABLE 8. Premature Ovarian Failure and Fragile X


FRAXA Premutation

Sporadic POF

2/122 (1.6%)

Familial POF

4/25 (16%)



Data of Murray and colleagues.
POF, premature ovarian failure.


The consensus seems to be that FRAXA is associated with POF. However, Kennerson and colleagues94 do not agree. They argue that data are best explained by a contiguous gene syndrome. That is, they postulate two separate but closely linked loci. Both may or may not be deleted in a given individual. That Xq27-28 contains both FMR-1 (FRAXA) and a region important for ovarian maintenance is consistent with, but does not prove, this hypothesis.

Myotonic Dystrophy and Expansion of Triplet Repeats (CTG)

Myotonic dystrophy is an autosomal dominant disorders are characterized by muscle wasting (head, neck, extremities), frontal balding, cataracts, and male hypogonadism (80%) caused by testicular atrophy. Female hypogonadism is much less common, if increased at all. Despite frequent textual citations, ovarian failure is actually not well documented.

Pathogenesis of myotonic dystrophy involves nucleotide expansion of CTG in the 3[prime] untranslated region of a protein located on chromosome 19. Normally, 5 to 27 CTG repeats are present. Heterozygotes usually have at least 50 repeats; severely affected individuals show 600 or more. As in FRAXA, poor response to ovulation induction regions is observed. Sermon and colleagues95 report fewer embryos per cycle than in standard ART; thus, pregnancy rates in preimplantation genetic diagnosis are decreased.

Premature Ovarian Failure and Polyglandular Autoimmune Syndrome

Type 1 polyglandular autoimmune syndrome is an autosomal recessive disorder characterized by deficiencies of the parathyroids, adrenals and gonad exist; moniliasis secondary to immune deficiencies is common. Hypergonadotropic ovarian failure occurs in 60% of cases. The disorder is common in Finland and in the Iranian Jewish population,96 but rare in other populations. Localized to human 2q22.3 the gene has a murine homologue: autoimmune regulation gene (AIRE).

Type II polyglandular autoimmune syndrome is also called Schmidt syndrome. Inheritance is autosomal dominant. Failure or hypofunction occurs in gonads, adrenals, thyroid, and pancreas. Hematologic, gastrointestinal, ocular, and integumental (hair) defects also occur; immunologic dysfunction is often pronounced.

Premature Ovarian Failure Associated with Anti-Ovarian Antibodies or Oophorities

Anti-ovarian antibodies may be either generalized in nature or directed against a specific cellular component (e.g., gonadotropin receptor, stromal cells, zona pellucida). Anasti97 reviewed the role of anti-ovarian antibodies in ovarian failure. In our opinion, a casual relation seems less likely than a secondary effect (epiphenomenon), antibodies arising only after ovarian damage has occurred for unrelated but primary reasons.

Similar reasoning applies to the hypothesis of oophoritis as a common cause of premature ovarian failure.

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