ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
Amenorrhea secondary to a vismodegib-induced blockade of follicle-stimulating hormone–receptor activation John Strasswimmer, M.D., Ph.D.,a,b,c Benjamin Latimer, B.S.,c and Steven Ory, M.D.d,e a
Melanoma and Cutaneous Oncology Program, Lynn Cancer Institute, Boca Raton Regional Hospital, Boca Raton; Department of Biochemistry, Florida Atlantic University, Boca Raton; c Dermatology Associates of the Palm Beaches, Delray Beach; d IVF Florida, Margate; and e Department of Obstetrics and Gynecology, Florida International University, Miami, Florida b
Objective: To report a novel mechanism suggestive of early ovarian failure secondary to the anti-tumor hedgehog-pathway inhibitor vismodegib. Design: Case report and literature review. Setting: Academic and private dermatology and fertility practices. Patient(s): A 34-year-old nulliparous woman with locally advanced basal cell carcinomas who became amenorrheic while receiving oral therapy with vismodegib. Intervention(s): Physical examination and endocrine evaluation. Main Outcome Measure(s): Elevated follicle-stimulating hormone (FSH) and low estrogen in the setting of a normal anti-M€ ullerian hormone. Result(s): FSH was elevated; estrogen was low. Preantral follicles were detected and anti-M€ ullerian hormone activity was normal. Menses resumed 5 weeks after cessation of therapy. Conclusion(s): Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway is indicated for advanced basal cell carcinoma and is associated with amenorrhea. The mechanism is unknown; it has some features of ovarian failure but preserves ovarian potential through blockading of FSH-receptor–dependent signal transduction. This effect appears to be rapidly reversible upon cessation of therapy. Vismodegib and related compounds may have potential for a role in intervention for gynecologic and endocrine disorders and in therapy for other issues involving FSHUse your smartphone dependent function. (Fertil SterilÒ 2014;-:-–-. Ó2014 by American Society for to scan this QR code Reproductive Medicine.) and connect to the Key Words: Vismodegib, FSH-R, amenorrhea, BCC, hedgehog Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/strasswimmer-amenorrhea-vismodegib-blockade-fshr/
V
ismodegib is a novel oral medication that targets the hedgehog (Hh) pathway of signaling molecules and is indicated for treatment of basal cell carcinoma (BCC) (1). This type of carcinoma and other
tumors are associated with mutations in the Hh pathway. Amenorrhea is a reported side effect of vismodegib therapy. Hedgehog molecules are best characterized by their role in embryogenesis, where they are expressed at
Received October 13, 2013; revised April 27, 2014; accepted April 29, 2014. J.S. and S.O. have a patent pending on a method for modulation of follicle-stimulating hormone– receptor activation. B.L. has nothing to disclose. A portion of this article was presented in oral format at the 2014 American Academy of Dermatology Annual Conference, Denver, Colorado, March 22, 2014. Reprint requests: John Strasswimmer, M.D., Ph.D., 2605 West Atlantic Ave., # D-204, Delray Beach, Florida 33445 (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.04.045 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
epithelial–mesenchymal boundaries in developing organs. The Hh pathway is essential for the proper development of the lungs, gut, pancreas, hair follicles, and teeth. The role of these molecules in adult physiology is poorly characterized, although they are expressed in regenerating tissue. Recently, the Hh pathway was demonstrated to be important in ovarian steroidogenesis (2). Hedgehog molecules exert their paracrine or autocrine function through binding to the transmembrane protein Patched, which in turn 1
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY modulates the activity of the G-protein–coupled membrane molecule Smoothened, which leads to translocation of the Gli transcription factor from the cytoplasm to the nucleus, and to altered target gene expression. By inhibiting Smoothened, vismodegib interrupts this signal transduction pathway, leading to tumor shrinkage. Vismodegib is indicated for treatment of advanced BCC, a common dermatologic malignancy. It is one of several agents that target the Hh pathway, which has been implicated in playing a role in a variety of malignancies (3). For BCC treatment with vismodegib, the medication needs to be continued indefinitely or until treatment failure. Therefore, any side effects need to be managed over a multi-year time frame. Amenorrhea was reported in 3 of 10 women of reproductive age in a pivotal phase II study (1), but the pathophysiology is unknown. The study authors and the sponsoring company were not able to provide any additional information. The current article describes novel evidence in one such patient that vismodegib interrupts the folliclestimulating hormone receptor (FSH-R)–dependent signaling at the oocyte.
MATERIALS AND METHODS A 34-year-old nulliparous woman with BCC nevus syndrome presented with locally advanced BCC, including an infiltrating tumor overlying the carotid sheath area which had previously undergone multiple surgeries and radiation therapy. Her history was significant for lymphoma at age 11 years; she had been treated with chemotherapy, radiation, and surgery, and also for mild well-controlled hypothyroidism. She experienced menarche at age 13 years and had regular menses at intervals of 30–35 days. One month after commencement of vismodegib therapy, she became amenorrheic. At 2 months, her tumors demonstrated clinical remission, which has persisted to date. She remained amenorrheic after 20 months of continuous therapy, which was discontinued because of her severe weight loss and fatigue. Five weeks after cessation of therapy, she resumed menses.
RESULTS Pelvic examination revealed atrophic vaginal changes consistent with a hypoestrogen state. Ultrasonography revealed a small, retroflexed uterus with a small pedunculated leiomyoma and normal ovaries, with multiple bilateral preantral follicles. Of note, the leiomyoma measured 5.89 cm, which was smaller than the previous ultrasound measurement of 7.2 cm, which was obtained 6 months before initiation of vismodegib therapy. Results of reproductive endocrine testing were unique and novel (Table 1). Her elevated FSH and low estrogen level were indicative of markedly diminished ovarian functioning. However, the presence of preantral follicles and the antiM€ ullerian hormone value indicate preservation of normal ovarian potential and a possible reversal of effect after cessation of therapy. Because her physical and endocrine findings demonstrated functional ovarian failure, she began appropriate menopause management, including bone-density and lipid2
TABLE 1 Reproductive endocrine evaluation in a patient undergoing vismodegib therapy. Hormone € llerian hormone, Antimu ng/mL Luteinizing hormone, IU/L Follicle-stimulating hormone, IU/L Estradiol, pg/mL Progesterone, ng/mL
Level 2.6 25.3 16.0 26.9 0.4
Normal range
Amenorrhea secondary to a vismodegib-induced blockade of follicle-stimulating hormone–receptor activation John Strasswimmer, M.D., Ph.D.,a,b,c Benjamin Latimer, B.S.,c and Steven Ory, M.D.d,e a
Melanoma and Cutaneous Oncology Program, Lynn Cancer Institute, Boca Raton Regional Hospital, Boca Raton; Department of Biochemistry, Florida Atlantic University, Boca Raton; c Dermatology Associates of the Palm Beaches, Delray Beach; d IVF Florida, Margate; and e Department of Obstetrics and Gynecology, Florida International University, Miami, Florida b
Objective: To report a novel mechanism suggestive of early ovarian failure secondary to the anti-tumor hedgehog-pathway inhibitor vismodegib. Design: Case report and literature review. Setting: Academic and private dermatology and fertility practices. Patient(s): A 34-year-old nulliparous woman with locally advanced basal cell carcinomas who became amenorrheic while receiving oral therapy with vismodegib. Intervention(s): Physical examination and endocrine evaluation. Main Outcome Measure(s): Elevated follicle-stimulating hormone (FSH) and low estrogen in the setting of a normal anti-M€ ullerian hormone. Result(s): FSH was elevated; estrogen was low. Preantral follicles were detected and anti-M€ ullerian hormone activity was normal. Menses resumed 5 weeks after cessation of therapy. Conclusion(s): Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway is indicated for advanced basal cell carcinoma and is associated with amenorrhea. The mechanism is unknown; it has some features of ovarian failure but preserves ovarian potential through blockading of FSH-receptor–dependent signal transduction. This effect appears to be rapidly reversible upon cessation of therapy. Vismodegib and related compounds may have potential for a role in intervention for gynecologic and endocrine disorders and in therapy for other issues involving FSHUse your smartphone dependent function. (Fertil SterilÒ 2014;-:-–-. Ó2014 by American Society for to scan this QR code Reproductive Medicine.) and connect to the Key Words: Vismodegib, FSH-R, amenorrhea, BCC, hedgehog Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/strasswimmer-amenorrhea-vismodegib-blockade-fshr/
V
ismodegib is a novel oral medication that targets the hedgehog (Hh) pathway of signaling molecules and is indicated for treatment of basal cell carcinoma (BCC) (1). This type of carcinoma and other
tumors are associated with mutations in the Hh pathway. Amenorrhea is a reported side effect of vismodegib therapy. Hedgehog molecules are best characterized by their role in embryogenesis, where they are expressed at
Received October 13, 2013; revised April 27, 2014; accepted April 29, 2014. J.S. and S.O. have a patent pending on a method for modulation of follicle-stimulating hormone– receptor activation. B.L. has nothing to disclose. A portion of this article was presented in oral format at the 2014 American Academy of Dermatology Annual Conference, Denver, Colorado, March 22, 2014. Reprint requests: John Strasswimmer, M.D., Ph.D., 2605 West Atlantic Ave., # D-204, Delray Beach, Florida 33445 (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.04.045 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
epithelial–mesenchymal boundaries in developing organs. The Hh pathway is essential for the proper development of the lungs, gut, pancreas, hair follicles, and teeth. The role of these molecules in adult physiology is poorly characterized, although they are expressed in regenerating tissue. Recently, the Hh pathway was demonstrated to be important in ovarian steroidogenesis (2). Hedgehog molecules exert their paracrine or autocrine function through binding to the transmembrane protein Patched, which in turn 1
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY modulates the activity of the G-protein–coupled membrane molecule Smoothened, which leads to translocation of the Gli transcription factor from the cytoplasm to the nucleus, and to altered target gene expression. By inhibiting Smoothened, vismodegib interrupts this signal transduction pathway, leading to tumor shrinkage. Vismodegib is indicated for treatment of advanced BCC, a common dermatologic malignancy. It is one of several agents that target the Hh pathway, which has been implicated in playing a role in a variety of malignancies (3). For BCC treatment with vismodegib, the medication needs to be continued indefinitely or until treatment failure. Therefore, any side effects need to be managed over a multi-year time frame. Amenorrhea was reported in 3 of 10 women of reproductive age in a pivotal phase II study (1), but the pathophysiology is unknown. The study authors and the sponsoring company were not able to provide any additional information. The current article describes novel evidence in one such patient that vismodegib interrupts the folliclestimulating hormone receptor (FSH-R)–dependent signaling at the oocyte.
MATERIALS AND METHODS A 34-year-old nulliparous woman with BCC nevus syndrome presented with locally advanced BCC, including an infiltrating tumor overlying the carotid sheath area which had previously undergone multiple surgeries and radiation therapy. Her history was significant for lymphoma at age 11 years; she had been treated with chemotherapy, radiation, and surgery, and also for mild well-controlled hypothyroidism. She experienced menarche at age 13 years and had regular menses at intervals of 30–35 days. One month after commencement of vismodegib therapy, she became amenorrheic. At 2 months, her tumors demonstrated clinical remission, which has persisted to date. She remained amenorrheic after 20 months of continuous therapy, which was discontinued because of her severe weight loss and fatigue. Five weeks after cessation of therapy, she resumed menses.
RESULTS Pelvic examination revealed atrophic vaginal changes consistent with a hypoestrogen state. Ultrasonography revealed a small, retroflexed uterus with a small pedunculated leiomyoma and normal ovaries, with multiple bilateral preantral follicles. Of note, the leiomyoma measured 5.89 cm, which was smaller than the previous ultrasound measurement of 7.2 cm, which was obtained 6 months before initiation of vismodegib therapy. Results of reproductive endocrine testing were unique and novel (Table 1). Her elevated FSH and low estrogen level were indicative of markedly diminished ovarian functioning. However, the presence of preantral follicles and the antiM€ ullerian hormone value indicate preservation of normal ovarian potential and a possible reversal of effect after cessation of therapy. Because her physical and endocrine findings demonstrated functional ovarian failure, she began appropriate menopause management, including bone-density and lipid2
TABLE 1 Reproductive endocrine evaluation in a patient undergoing vismodegib therapy. Hormone € llerian hormone, Antimu ng/mL Luteinizing hormone, IU/L Follicle-stimulating hormone, IU/L Estradiol, pg/mL Progesterone, ng/mL
Level 2.6 25.3 16.0 26.9 0.4
Normal range
