Case Report Spontaneous Recovery of Ovarian Function in an Adolescent with Galactosemia and Apparent Premature Ovarian Insufficiency Paul Davies MD 1, Ellen Connor MD 2, Jennifer MacKenzie MD 3, Mary Anne Jamieson MD 1,* 1
Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada Department of Pediatric Endocrinology, University of Wisconsin, Madison, Wisconsin 3 Department of Medical Genetics, Queens University, Kingston, Ontario, Canada 2
a b s t r a c t Background: Galactosemia is an inborn error of metabolism resulting in premature ovarian insufficiency in 80-90% of females. There have been no reported cases of biochemical ovarian failure followed by normal menses. Case: A 12-year-old girl with galactosemia presented for gynecologic consultation. Her follicle-stimulating hormone (FSH) and estradiol levels were 52.9 U/L and less than 100 pmol/L, respectively. She started exogenous estrogen to stimulate puberty. At 16, she had spontaneous regular menstrual cycles. FSH and luteinizing hormone (LH) levels reflected normal ovarian function. Hormonal contraception was € llerian hormone provided. One year later, she was found to be in ovarian failure (FSH 86.6 U/L, LH 33.3 U/L), and both estradiol and anti-Mu were undetectable. Summary and Conclusions: This case documents spontaneous resumption of ovarian function after galactosemia-related ovarian failure. The use of FSH and LH is potentially limited in predicting ovarian function in this population. Key Words: Galactosemia, Primary Ovarian Insufficiency, Ovarian Failure, Delayed Puberty, Hypergonadotropic Hypogonadism, Antimullerian Hormone
Introduction
Case
Classic galactosemia is an autosomal recessive, inborn error of galactose metabolism caused by mutations in galactose-1-phosphate uridyltransferase (GALT). The resulting deficiency of GALT results in elevated galactose levels in the newborn.1 Elevated galactose levels in the neonatal period can have significant consequences, including sepsis, hepatocellular damage, failure to thrive, bleeding difficulties, and death. Rapid treatment with a lactose and galactoseerestricted diet reverses these consequences and prevents long-term intellectual disability. However, despite optimal therapy, individuals can have lifelong sequelae, including learning disabilities, motor difficulties, and premature ovarian insufficiency/failure (POI/POF). Case reports of pregnancy in women with galactosemia are well documented.2e4 In some rare circumstances, spontaneous conception has occurred after a diagnosis of POF has been made, with a hormonal profile suggesting a lack of reproductive ovarian function. Other studies report girls developing normally through puberty, with subsequent irregular menses and spontaneous conception. In all case reports of pregnancy after oligo- or amenorrhea, none had subsequent regular menses after pregnancy. There have been no reported cases of confirmed biochemical ovarian failure in adolescence, followed by the development of normal menstrual cycles.
A 12-year-old girl presented for routine consultation to the Pediatric and Adolescent Gynecology Clinic with a known diagnosis of galactosemia. Her past history included presentation with lethargy, vomiting, jaundice, and hepatomegaly at 1 week of age. Symptoms resolved after the initiation of a strict galactose-restricted diet. At approximately 6 years of age, she was diagnosed with a learning disability, and unfortunately, cataracts developed in the right and left eyes at about 7 and 11 years of age, respectively. She continued on a strict galactose-restricted diet supervised by a metabolic dietician with some difficulties with compliance. Past genetic testing had revealed that the patient was homozygous for the p.Gln188Arg (c.563AOG) missense mutation in GALT. This is the most common mutation found in classic galactosemia, which alters the active site, disrupting the normal function of the GALT enzyme.5 The patient's GALT enzyme activity was zero. This mutation has been associated with increased risk for premature ovarian insufficiency.6 At the time of adolescent gynecologic evaluation, adrenarche was present, consistent with normal adrenal function, which is not disrupted by galactosemia. She did not have evidence of thelarche or virilization, and her height and weight were less than the third percentile. Her laboratory results included a follicle-stimulating hormone (FSH) level of 52.9 U/L (postmenopausal 30-130 U/L) and an estradiol level below the laboratory limit of detection of 100 pmol/L. Her luteinizing hormone (LH) level of 8.2 U/L was not elevated (postmenopausal 15-70 U/L). It was unclear, and still is, whether this is a significant finding.
The authors indicate no conflicts of interest. * Address correspondence to: Dr Mary Anne Jamieson, MD, Department of Obstetrics and Gynecology, Queen's University, Kingston, ON K7L3N6, Canada E-mail address: [email protected] (M.A. Jamieson).
1083-3188/$ - see front matter Ó 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2014.09.003
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P. Davies et al. / J Pediatr Adolesc Gynecol 28 (2015) e101ee103
She began exogenous hormone therapy to mimic pubertal initiation, progression, and then ultimately menarche in a “start slow and go slow” fashion. She was initially prescribed 25 mg of estradiol transdermally. At 4 months, her dose was increased to 50 mg. At the next 4-month follow-up, she requested a change from the patch formulation and was switched to estradiol 0.06% topical gel 3 pumps/day. After 5 months at a dosage of 3 pumps/day, her dosage was increased to 4 pumps/day (considered reproductive dosing). After a course of 17 months of exogenous estrogen therapy, her height and weight were at the 10th percentile. She had Tanner stage 3 breasts and pubic hair. After 4 months of receiving reproductive estrogen gel doses and not having experienced any vaginal bleeding, she was given a course of 200 mg of oral progesterone once daily for 12 days. She did not bleed with the first course of progesterone. Reassurance was given because this result was thought to be the result of insufficient endometrial proliferation. Eight months later, a second attempt at a course of oral progesterone successfully induced a withdrawal bleed. There had been no bleeding in the interim. She was counseled to continue progesterone use every 3 months with daily estradiol gel and was recommended to have yearly follow-up. She returned to the clinic just before her 16th birthday. It had been 2 years since her first course of progesterone. During the past year, she admitted to having regular, monthly menstrual cycles without progesterone use. She described molimina in the form of breast tenderness and pelvic cramping and a reported 5 days of menstrual flow. Her compliance had been suboptimal in regard to estrogen therapy. She was asked to refrain from estrogen therapy completely for 2 weeks so that blood work could be obtained to investigate ovarian function. Repeat FSH and LH levels were found to be 14 U/L and 3 U/L, respectively, both reflective of normal ovarian function. Estradiol and progesterone therapies were discontinued. Almost 1 year later, she continued to have monthly menstrual cycles, with classic moliminal symptoms. She became coital. Despite her obvious risk of future relapse into ovarian failure, normal cycles suggested a potential for pregnancy, so she chose to use contraception. In an attempt to avoid lactose-containing combined oral contraceptives, transdermal and vaginal ring products were tried but she did not find them satisfactory. All involved were aware that these contraceptive options would mask the presence or absence of endogenous ovarian function and spontaneous menses. Due to her strong preference, she began the use of depomedroxyprogesterone acetate (DMPA), knowing that estrogen-free therapy would be inappropriate if ovarian failure recurred. Given the amenorrhea rates on DMPA, she was asked to report estrogen-withdrawal symptoms (eg, hot flushes, night sweats, vaginal dryness) to monitor for possible ovarian failure. Even though she was not considering future fertility at this time, a consultation was offered to a fertility specialist for her and her family to gather information. She was seen in follow-up after 4 months to assess her satisfaction with DMPA. She had tolerated the first injection
with no ill effects but had not received the second injection (1 month late). Her hormonal profile was rechecked (an € llerian hormone [AMH] level was drawn for the first anti-Mu time). The gonadotropin results showed that she was again in ovarian failure. Her FSH was 86.6 U/L, LH was 33.3 U/L and both estradiol and AMH were undetectable. At this juncture, ideal management is unclear. She would consider pregnancy to be devastating at her current age and in her current relationship status, but pregnancy is extremely unlikely with these FSH and LH levels, as well as an undetectable AMH level (!0.57). AMH correlates with ovarian reserve, and its measure has proved useful in assessing reproductive potential. She may choose to continue DMPA and estrogen gel (4 pumps per day). Bone mineral density will be followed. Summary and Conclusion
Premature ovarian insufficiency is the most common long-term complication seen in females with classic galactosemia and occurs in 80-90% of such patients.7 Premature ovarian failure commonly presents clinically with the absence of spontaneous puberty; however, in those who do have ovarian function initially, menses are often irregular and may cease prematurely.8 Consequently, most girls and women with galactosemia are at risk for decreased bone mineral density and are faced with the potential inability to reproduce.9 This case documents apparent short-lived, spontaneous resumption of ovarian function and monthly menses after galactosemia-related ovarian failure, which has not previously been reported. Initial goals of management during the first documented presentation of ovarian failure included education and hormone replacement therapy for normal pubertal development and the establishment of menses, as well as optimization of height and bone and cardiac health. When the patient began having spontaneous menses without progesterone withdrawal therapy and had normal FSH and LH levels, management goals were amended. AMH was not assessed at that time, but in retrospect could perhaps have indicated impending loss of remaining ovarian reserve. During the months when our patient seemingly had resumed ovarian function, reliable pregnancy prevention was of paramount importance to her and lactose-free contraceptives were used. The patient now has laboratory values again consistent with ovarian failure, and the AMH level suggests permanency. However, a single case report of spontaneous pregnancy despite undetectable AMH levels exists.2 Before her second clinical presentation of POF and confirmation with an undetectable AMH level, referral was made to a fertility program to discuss advanced reproductive technologies, ovum donation or ovarian tissue cryopreservation, and whether the latter would be appropriate for a patient with galactosemia. It should be noted, however, that spontaneous pregnancy is a possibility with galactosemia and patients should be counseled accordingly. In 2008, Gubbels et al reviewed the literature pertaining to classic galactosemia and spontaneous pregnancy. In 1 study, 22 galactosemic women were followed. Nine women had
P. Davies et al. / J Pediatr Adolesc Gynecol 28 (2015) e101ee103
tried to conceive, of whom 4 were successful. They found 50 reported cases in total at that time, which reveals that there is a definite possibility of spontaneous pregnancy in those with classic galactosemia.10 As expected, an accurate spontaneous conception rate would be difficult to determine because, previously, many patients were told they had no chances of conceiving. Therefore, they may not have tried.9 The topic of fertility preservation in this patient population does not come without controversy. Specifically, this pertains to the techniques used, the age at which they are applied, and the potential cognitive effects these young women may experience. Until recently, there had been little guidance in the literature as to how to appropriately counsel these families. In 2013, van Erven et al published a report affording recommendations based on expert opinion. They concluded that it should be emphasized that spontaneous pregnancy can occur despite POI, that consultation with an ethics committee should be obtained if there is consideration of assisted reproductive technologies, and that if fertility preservation were to be pursued, cryopreservation of ovarian tissue at an early prepubertal age might be the best option, even though at this time it is still experimental.9 Currently, little evidence of success of reproductive technologies in the galactosemia population exists, and the “experimental” technologies, even if deemed appropriate in a child, are seldom readily available. This case underscores the limitations of the use of FSH and LH to predict ovarian function and the need to use other measurements and clinical acumen in assessing ovarian reserve. It seems plausible that perhaps some ovarian function remained during the initial episode of POI, and perhaps AMH could have indicated the likelihood that this would last. One possible explanation for resumed ovarian function was improved compliance with a galactoserestricted diet. However, there is little evidence to suggest
e103
dietary compliance, after infancy, influences ovarian function.11 Alternatively, perhaps menstrual bleeding that was occurring spontaneously was anovulatory, as is sometimes seen in young adolescent girls, despite a relatively “regular” pattern. Perhaps laboratory error or assay limitations contributed to the elevation in the first FSH value or the improvements in the subsequent FSH and LH values; this possibility seems less likely due to the symptoms the patient had on presentation that were consistent with POI. Prediction of ovarian function is of significance and concern to young women at high risk for POF, including those with galactosemia, Turner syndrome, and fragile X and underscores the need to increase our diagnostic strategies with AMH or other emerging tools.
References 1. Berry G: Galactoemia and amenorrhea in the adolescent. Ann N Y Acad Sci 2008; 1135:112 2. Gubbels C, Kuppens S, Bakker J, et al: Pregnancy in classic galactosemia despite undetectable anti-Mullerian hormone. Fertil Steril 2009; 91:1293.e13 3. Forges T, Monnier P, Lehup B, et al: Ovarian tissue cryopreservation and subsequent spontaneous pregnancies in a patient with classic galactosemia. Fertil Steril 2011; 95:290.e1 4. Schadewaldt P, Hammen H, Kamalanathan L, et al: Biochemical monitoring of pregnancy and breast feeding in five patients with classical galactosaemiaeand review of the literature. Eur J Pediatr 2009; 168:721 5. Calderon F, Pharsalker A, Crocket D, et al: Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene. Hum Mutat 2007; 28: 939 6. Rubio-Gozalbo M, Gubbels C, Bakker J, et al: Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update 2010; 16:177 7. Fridovich-Keil J, Gubbels C, Spencer J, et al: Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 2011; 34:357 8. Spencer J, Badik J, Ryan E, et al: Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab 2013; 98:E1257 9. van Erven B, Gubbels C, van Golde R, et al: Fertility preservation in female classic galactosemia patients. Orphanet J Rare Dis 2013; 8:107 10. Gubbels C, Land J, Rubio-Gozalbo M: Fertility and impact of pregnancies on the mother and child in classic galactosemia. Ostet Gynecol Surv 2008; 63:334 11. Van Calcar S, Bernstein L, Frances J, et al: A re-evaluation of life-long galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab 2014; 112:191
Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada Department of Pediatric Endocrinology, University of Wisconsin, Madison, Wisconsin 3 Department of Medical Genetics, Queens University, Kingston, Ontario, Canada 2
a b s t r a c t Background: Galactosemia is an inborn error of metabolism resulting in premature ovarian insufficiency in 80-90% of females. There have been no reported cases of biochemical ovarian failure followed by normal menses. Case: A 12-year-old girl with galactosemia presented for gynecologic consultation. Her follicle-stimulating hormone (FSH) and estradiol levels were 52.9 U/L and less than 100 pmol/L, respectively. She started exogenous estrogen to stimulate puberty. At 16, she had spontaneous regular menstrual cycles. FSH and luteinizing hormone (LH) levels reflected normal ovarian function. Hormonal contraception was € llerian hormone provided. One year later, she was found to be in ovarian failure (FSH 86.6 U/L, LH 33.3 U/L), and both estradiol and anti-Mu were undetectable. Summary and Conclusions: This case documents spontaneous resumption of ovarian function after galactosemia-related ovarian failure. The use of FSH and LH is potentially limited in predicting ovarian function in this population. Key Words: Galactosemia, Primary Ovarian Insufficiency, Ovarian Failure, Delayed Puberty, Hypergonadotropic Hypogonadism, Antimullerian Hormone
Introduction
Case
Classic galactosemia is an autosomal recessive, inborn error of galactose metabolism caused by mutations in galactose-1-phosphate uridyltransferase (GALT). The resulting deficiency of GALT results in elevated galactose levels in the newborn.1 Elevated galactose levels in the neonatal period can have significant consequences, including sepsis, hepatocellular damage, failure to thrive, bleeding difficulties, and death. Rapid treatment with a lactose and galactoseerestricted diet reverses these consequences and prevents long-term intellectual disability. However, despite optimal therapy, individuals can have lifelong sequelae, including learning disabilities, motor difficulties, and premature ovarian insufficiency/failure (POI/POF). Case reports of pregnancy in women with galactosemia are well documented.2e4 In some rare circumstances, spontaneous conception has occurred after a diagnosis of POF has been made, with a hormonal profile suggesting a lack of reproductive ovarian function. Other studies report girls developing normally through puberty, with subsequent irregular menses and spontaneous conception. In all case reports of pregnancy after oligo- or amenorrhea, none had subsequent regular menses after pregnancy. There have been no reported cases of confirmed biochemical ovarian failure in adolescence, followed by the development of normal menstrual cycles.
A 12-year-old girl presented for routine consultation to the Pediatric and Adolescent Gynecology Clinic with a known diagnosis of galactosemia. Her past history included presentation with lethargy, vomiting, jaundice, and hepatomegaly at 1 week of age. Symptoms resolved after the initiation of a strict galactose-restricted diet. At approximately 6 years of age, she was diagnosed with a learning disability, and unfortunately, cataracts developed in the right and left eyes at about 7 and 11 years of age, respectively. She continued on a strict galactose-restricted diet supervised by a metabolic dietician with some difficulties with compliance. Past genetic testing had revealed that the patient was homozygous for the p.Gln188Arg (c.563AOG) missense mutation in GALT. This is the most common mutation found in classic galactosemia, which alters the active site, disrupting the normal function of the GALT enzyme.5 The patient's GALT enzyme activity was zero. This mutation has been associated with increased risk for premature ovarian insufficiency.6 At the time of adolescent gynecologic evaluation, adrenarche was present, consistent with normal adrenal function, which is not disrupted by galactosemia. She did not have evidence of thelarche or virilization, and her height and weight were less than the third percentile. Her laboratory results included a follicle-stimulating hormone (FSH) level of 52.9 U/L (postmenopausal 30-130 U/L) and an estradiol level below the laboratory limit of detection of 100 pmol/L. Her luteinizing hormone (LH) level of 8.2 U/L was not elevated (postmenopausal 15-70 U/L). It was unclear, and still is, whether this is a significant finding.
The authors indicate no conflicts of interest. * Address correspondence to: Dr Mary Anne Jamieson, MD, Department of Obstetrics and Gynecology, Queen's University, Kingston, ON K7L3N6, Canada E-mail address: [email protected] (M.A. Jamieson).
1083-3188/$ - see front matter Ó 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2014.09.003
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P. Davies et al. / J Pediatr Adolesc Gynecol 28 (2015) e101ee103
She began exogenous hormone therapy to mimic pubertal initiation, progression, and then ultimately menarche in a “start slow and go slow” fashion. She was initially prescribed 25 mg of estradiol transdermally. At 4 months, her dose was increased to 50 mg. At the next 4-month follow-up, she requested a change from the patch formulation and was switched to estradiol 0.06% topical gel 3 pumps/day. After 5 months at a dosage of 3 pumps/day, her dosage was increased to 4 pumps/day (considered reproductive dosing). After a course of 17 months of exogenous estrogen therapy, her height and weight were at the 10th percentile. She had Tanner stage 3 breasts and pubic hair. After 4 months of receiving reproductive estrogen gel doses and not having experienced any vaginal bleeding, she was given a course of 200 mg of oral progesterone once daily for 12 days. She did not bleed with the first course of progesterone. Reassurance was given because this result was thought to be the result of insufficient endometrial proliferation. Eight months later, a second attempt at a course of oral progesterone successfully induced a withdrawal bleed. There had been no bleeding in the interim. She was counseled to continue progesterone use every 3 months with daily estradiol gel and was recommended to have yearly follow-up. She returned to the clinic just before her 16th birthday. It had been 2 years since her first course of progesterone. During the past year, she admitted to having regular, monthly menstrual cycles without progesterone use. She described molimina in the form of breast tenderness and pelvic cramping and a reported 5 days of menstrual flow. Her compliance had been suboptimal in regard to estrogen therapy. She was asked to refrain from estrogen therapy completely for 2 weeks so that blood work could be obtained to investigate ovarian function. Repeat FSH and LH levels were found to be 14 U/L and 3 U/L, respectively, both reflective of normal ovarian function. Estradiol and progesterone therapies were discontinued. Almost 1 year later, she continued to have monthly menstrual cycles, with classic moliminal symptoms. She became coital. Despite her obvious risk of future relapse into ovarian failure, normal cycles suggested a potential for pregnancy, so she chose to use contraception. In an attempt to avoid lactose-containing combined oral contraceptives, transdermal and vaginal ring products were tried but she did not find them satisfactory. All involved were aware that these contraceptive options would mask the presence or absence of endogenous ovarian function and spontaneous menses. Due to her strong preference, she began the use of depomedroxyprogesterone acetate (DMPA), knowing that estrogen-free therapy would be inappropriate if ovarian failure recurred. Given the amenorrhea rates on DMPA, she was asked to report estrogen-withdrawal symptoms (eg, hot flushes, night sweats, vaginal dryness) to monitor for possible ovarian failure. Even though she was not considering future fertility at this time, a consultation was offered to a fertility specialist for her and her family to gather information. She was seen in follow-up after 4 months to assess her satisfaction with DMPA. She had tolerated the first injection
with no ill effects but had not received the second injection (1 month late). Her hormonal profile was rechecked (an € llerian hormone [AMH] level was drawn for the first anti-Mu time). The gonadotropin results showed that she was again in ovarian failure. Her FSH was 86.6 U/L, LH was 33.3 U/L and both estradiol and AMH were undetectable. At this juncture, ideal management is unclear. She would consider pregnancy to be devastating at her current age and in her current relationship status, but pregnancy is extremely unlikely with these FSH and LH levels, as well as an undetectable AMH level (!0.57). AMH correlates with ovarian reserve, and its measure has proved useful in assessing reproductive potential. She may choose to continue DMPA and estrogen gel (4 pumps per day). Bone mineral density will be followed. Summary and Conclusion
Premature ovarian insufficiency is the most common long-term complication seen in females with classic galactosemia and occurs in 80-90% of such patients.7 Premature ovarian failure commonly presents clinically with the absence of spontaneous puberty; however, in those who do have ovarian function initially, menses are often irregular and may cease prematurely.8 Consequently, most girls and women with galactosemia are at risk for decreased bone mineral density and are faced with the potential inability to reproduce.9 This case documents apparent short-lived, spontaneous resumption of ovarian function and monthly menses after galactosemia-related ovarian failure, which has not previously been reported. Initial goals of management during the first documented presentation of ovarian failure included education and hormone replacement therapy for normal pubertal development and the establishment of menses, as well as optimization of height and bone and cardiac health. When the patient began having spontaneous menses without progesterone withdrawal therapy and had normal FSH and LH levels, management goals were amended. AMH was not assessed at that time, but in retrospect could perhaps have indicated impending loss of remaining ovarian reserve. During the months when our patient seemingly had resumed ovarian function, reliable pregnancy prevention was of paramount importance to her and lactose-free contraceptives were used. The patient now has laboratory values again consistent with ovarian failure, and the AMH level suggests permanency. However, a single case report of spontaneous pregnancy despite undetectable AMH levels exists.2 Before her second clinical presentation of POF and confirmation with an undetectable AMH level, referral was made to a fertility program to discuss advanced reproductive technologies, ovum donation or ovarian tissue cryopreservation, and whether the latter would be appropriate for a patient with galactosemia. It should be noted, however, that spontaneous pregnancy is a possibility with galactosemia and patients should be counseled accordingly. In 2008, Gubbels et al reviewed the literature pertaining to classic galactosemia and spontaneous pregnancy. In 1 study, 22 galactosemic women were followed. Nine women had
P. Davies et al. / J Pediatr Adolesc Gynecol 28 (2015) e101ee103
tried to conceive, of whom 4 were successful. They found 50 reported cases in total at that time, which reveals that there is a definite possibility of spontaneous pregnancy in those with classic galactosemia.10 As expected, an accurate spontaneous conception rate would be difficult to determine because, previously, many patients were told they had no chances of conceiving. Therefore, they may not have tried.9 The topic of fertility preservation in this patient population does not come without controversy. Specifically, this pertains to the techniques used, the age at which they are applied, and the potential cognitive effects these young women may experience. Until recently, there had been little guidance in the literature as to how to appropriately counsel these families. In 2013, van Erven et al published a report affording recommendations based on expert opinion. They concluded that it should be emphasized that spontaneous pregnancy can occur despite POI, that consultation with an ethics committee should be obtained if there is consideration of assisted reproductive technologies, and that if fertility preservation were to be pursued, cryopreservation of ovarian tissue at an early prepubertal age might be the best option, even though at this time it is still experimental.9 Currently, little evidence of success of reproductive technologies in the galactosemia population exists, and the “experimental” technologies, even if deemed appropriate in a child, are seldom readily available. This case underscores the limitations of the use of FSH and LH to predict ovarian function and the need to use other measurements and clinical acumen in assessing ovarian reserve. It seems plausible that perhaps some ovarian function remained during the initial episode of POI, and perhaps AMH could have indicated the likelihood that this would last. One possible explanation for resumed ovarian function was improved compliance with a galactoserestricted diet. However, there is little evidence to suggest
e103
dietary compliance, after infancy, influences ovarian function.11 Alternatively, perhaps menstrual bleeding that was occurring spontaneously was anovulatory, as is sometimes seen in young adolescent girls, despite a relatively “regular” pattern. Perhaps laboratory error or assay limitations contributed to the elevation in the first FSH value or the improvements in the subsequent FSH and LH values; this possibility seems less likely due to the symptoms the patient had on presentation that were consistent with POI. Prediction of ovarian function is of significance and concern to young women at high risk for POF, including those with galactosemia, Turner syndrome, and fragile X and underscores the need to increase our diagnostic strategies with AMH or other emerging tools.
References 1. Berry G: Galactoemia and amenorrhea in the adolescent. Ann N Y Acad Sci 2008; 1135:112 2. Gubbels C, Kuppens S, Bakker J, et al: Pregnancy in classic galactosemia despite undetectable anti-Mullerian hormone. Fertil Steril 2009; 91:1293.e13 3. Forges T, Monnier P, Lehup B, et al: Ovarian tissue cryopreservation and subsequent spontaneous pregnancies in a patient with classic galactosemia. Fertil Steril 2011; 95:290.e1 4. Schadewaldt P, Hammen H, Kamalanathan L, et al: Biochemical monitoring of pregnancy and breast feeding in five patients with classical galactosaemiaeand review of the literature. Eur J Pediatr 2009; 168:721 5. Calderon F, Pharsalker A, Crocket D, et al: Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene. Hum Mutat 2007; 28: 939 6. Rubio-Gozalbo M, Gubbels C, Bakker J, et al: Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update 2010; 16:177 7. Fridovich-Keil J, Gubbels C, Spencer J, et al: Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 2011; 34:357 8. Spencer J, Badik J, Ryan E, et al: Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab 2013; 98:E1257 9. van Erven B, Gubbels C, van Golde R, et al: Fertility preservation in female classic galactosemia patients. Orphanet J Rare Dis 2013; 8:107 10. Gubbels C, Land J, Rubio-Gozalbo M: Fertility and impact of pregnancies on the mother and child in classic galactosemia. Ostet Gynecol Surv 2008; 63:334 11. Van Calcar S, Bernstein L, Frances J, et al: A re-evaluation of life-long galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab 2014; 112:191
