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Original Studies |
Division of Endocrinology (B.B.M., I.J.P.A., W.B.), Hospital das Clinicas of The University of Sao Paulo School of Medicine, Sao Paulo, Brazil; The Green Center for Reproductive Biology Sciences and the Department of Obstetrics and Gynecology (S.A.), the Department of Molecular Genetics (D.W.R.), and the Department of Internal Medicine (J.D.W.), University of Texas Southwestern Medical Center, Dallas Texas 75235-8857
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Abstract |
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Introduction |
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Homozygous (or compound heterozygous) mutations that impair the function of 17HSD3 in genetic males decrease testosterone formation in the fetal testis, as a result of which virilization of the male external genitalia is deficient, and most affected infants are raised as females (2). The mutations characterized to date include twelve missense mutations, three splice junction abnormalities, and one frame shift mutation (3, 4).
Although 17HSD3 deficiency has profound phenotypic consequences in
genetic males, Rosler et al. (5) reported that women who are
homozygous for the R80Q mutation are asymptomatic. However, the R80Q
mutation gives rise to an enzyme with about 20 percent of normal
activity and is the least severe 17HSD3 mutation characterized to date
(6). To gain additional insight into the role of 17HSD3 in women, we
ascertained seven additional affected women who are sisters of males
with 17HSD3 deficiency. These women are from four unrelated Brazilian
families and include two compound heterozygotes (R80Q/326–1,G
C) and
five homozygotes (one R80Q/R80Q two E215D/E215D, and two 326–1,GC).
Three of these women have had problems with fertility, but two of them
were treated successfully.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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)
Family 1 (17HSD3 Sao Paulo 1). The propositus (3, 7) is a
46,XY woman who is compound heterozygote, carrying an R80Q 17HSD 3
mutation on one allele and a 326–1,GC 17HSD3 mutation on the other.
Two older sisters are compound heterozygotes at the same locus.
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Family 2 (17HSD3 Sao Paulo 3). The index case and a younger
sibling are 46,XY individuals who are homozygotes for the R80Q mutation
in the 17HSD 3 gene (3, 7), and the mother is a heterozygous carrier
for the same mutation (Fig. 1
).
Sister 2–1 is also homozygous for the R80Q mutation; she had telarche
and pubarche at age 11 and menarche at age 13. Menses are regular with
a 30-day cycle. She is unmarried and does not have an active sex life.
Breasts and pubic hair were Tanner stage V, and there was no hirsutism
or acne. The hormonal findings were compatible with a normal follicular
phase (Table 1).
Family 3 (17HSD3 Sao Paulo 4). The propositus, a homozygote
for the E215D mutation of the 17HSD3 gene, is a 46,XY man whose parents
are double first cousins; he changed social sex from female to male at
age 10 (3). One brother is affected, the mother is a heterozygous
carrier, and two sisters are homozygotes for the same mutation (Fig. 1).
Sister 3–1 underwent thelarche and pubarche at age 11 and menarche at
age 13. Severe pubertal acne subsided after a few years. Menses are
regular. She used contraceptives during an 8-month marriage and is now
divorced and does not have an active sex life. She has Tanner stage V
breasts and pubic hair and no hirsutism or acne. Hormones were measured
during the luteal phase (Table 1).
Sister 3–2 had thelarche and pubarche at age 11 and menarche at age
13. Menses were irregular thereafter. She married at age 16 and was
unable to become pregnant for a year. She did became pregnant after 6
months of treatment with clomiphene citrate and delivered a normal
child. A second child was born 16 months later without additional
treatment, and she then had two spontaneous miscarriages. Breasts and
pubic hair are Tanner stage V, and there is no hirsutism or acne. She
is now on oral contraceptives, as reflected in the hormonal
measurements (Table 1).
Family 4 (17HSD3 Sao Paulo 5). The 46,XY propositus, the
offspring of a first cousin marriage (Fig. 1), was examined at age 18
at another hospital because of the growth of facial and body hair,
enlargement of the clitoris, and development of facial and body acne.
Menarche had not occurred, and there was no breast development. No
diagnosis was made, and she was not treated. She was referred to the
Hospital das Clinicas at age 34. Psychological evaluation documented
female gender identity. She had generalized hirsutism, male pubic hair
(Tanner V), a 7-cm clitoris with separate urethral and vaginal
openings, no palpable breast tissue, gonads palpable in the inguinal
canals, and a blind-ending vagina. The finding of a serum
androstenedione of 1600 ng/dL and a serum testosterone of 202 ng/dL
established the diagnosis of 17HSD3 deficiency. The testes were
removed, and histological examination revealed arrested spermatogenic
arrest and Leydig cell hyperplasia; the epididymides and ductus
deferens were normal.
Sister 4–1, age 35, had a normal menarche at age 12 and subsequent regular menses. She became pregnant without difficulty and had three children.
Sister 4–2, age 28, had normal menarche and thelarche and has regular menses. She has been married for 11 years and has tried unsuccessfully to become pregnant for the last 3 years. She has not had a diagnostic workup. The husband has three children from a previous marriage.
Laboratory studies Serum
DHEA, DHEAS, testosterone, and androstenedione were assayed as described (8). Serum progesterone, estradiol, LH, and FSH were measured by immunofluorimetric assays (AutoDelfia, Wallac Oy, Turku, Finland).
For analyses of chromosomal karyotype 12 metaphase lymphocytes were examined for each subject. Genomic DNA was extracted from white blood cells as before (9) using a PE Applied Biosystems model 340 Nucleic Acid Extractor. Mutations in the 17HSD3 gene were detected by amplification of individual exons using the PCR and single-strand DNA conformation polymorphism (SSCP) analysis, and the nucleotides of exons suspected of harboring mutations on the basis of SSCP were sequenced using a thermostable DNA polymerase (3).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C) and two with
homozygous mutations (R80Q/R80Q and E215D/E215D). Family 4, previously
unreported, carries a previously characterized mutation
(326–1,GC)(3). The severity of impairment of 17HSD3 function in two
of these mutations is different when the mutant complementary DNAs
(cDNAs) are expressed in reporter cells; namely, the R80Q enzyme
retains about 20% of normal activity (6), whereas the E215D enzyme
appears to be totally inactive (3). The splice acceptor abnormality
(326–1,GC) has not been expressed, but splice acceptor
abnormalities usually preclude the synthesis of functional protein and
are typically associated with severe phenotypic defects (10, 11). The
compound heterozygote (R80Q/326–1,GC) would be predicted to have an
intermediate level of activity between that of the R80Q mutation and
undetectable. These in vitro assays of enzyme function
appear to have clinical relevance in that males with the R80Q mutation
are the only ones described to date in which the postpubertal testes
are capable of secreting significant amounts of testosterone (3, 12). An unexpected finding in this study was that three of seven affected women (subjects 1–1, 3–2, and 4–2) have had infertility problems. It is unlikely that loss of 17HSD3 activity predisposes to infertility because these women were endocrinologically normal at the time they were examined by us, because each woman with a fertility problem had a sister with the same mutations but normal fertility, and because 17HSD3 does not appear to be expressed in the normal human ovary (13). Such a conclusion is in keeping with the report by Rosler et al. (4) (and the findings in this study) that women who are homozygous for the R80Q mutation are endocrinologically normal.
However, other mutations in steroid hormone biosynthesis are known to cause inconsistent manifestations in affected women. For example, homozygous mutations in the 3ß-hydroxysteroid dehydrogenase type II gene cause male pseudohermaphroditism in boys and may either be cryptic or cause premature pubarche in women (14). Furthermore, one woman with polycystic ovarian disease has been reported who had elevated plasma androstenedione levels and was thought to have 17HSD deficiency (15), and 17HSD3 is expressed in the human ovary in some pathological states (16). Consequently, it is possible that deficiency in 17HSD3 may have contributed to the infertility in these women. If this is the case, 17HSD 3 must be expressed in some tissue(s) in normal women. Additional studies will have to be performed to determine whether this isoenzyme plays a role in female physiology.
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Footnotes |
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Received August 18, 1998.
Revised October 13, 1998.
Accepted November 3, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-reductase deficiency. Medicine. 75:64–76.[CrossRef][Medline]
-reductase 2 deficiency. J Clin
Invest. 90:799–809.
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