**3. Parasitic endocrine disruption; polycystic ovarian syndrome induced by neurocysticercosis**

## **3.1. Background**

There is growing awareness of the role of environmental endocrine disrupters in human health and reproduction as well as in the health and reproduction of other species. Most of the research in this area has dealt with the menace of manmade endocrine disrupting chemicals (EDC's), such as phthalates and hydraulic fracking chemicals. We are also rediscovering the endocrine disrupting role of parasites, which have preyed upon our species since prehistoric times. An example of this appears in statues of the pharaoh, Akhnaton which have often portrayed him as a young man with rounded hips and gynecomastia. Some historical epi‐ demiologists have suggested that this feminized appearance might be the result of hepatic involvement by schistosomiasis, which has long been endemic in the Nile Valley.

#### **3.2. PCOS induced by neurocysticercosis**

The patient we reported was a 33 year old (at that time) Mexican woman G3P2012 with extensive neurocysticercosis, who was referred to our clinic for secondary oligomenorrhea, acne, and hirsutism [49]. She had no localizing neurologic signs and none of the cestodes directly involved the hypothalamus or the pituitary gland. There was no family history of PCOS. She had previously conceived three times without difficulty, followed by 2 normal pregnancies and 1 elective abortion. Her BMI was 28.34 kg/m2 and was almost unchanged from 2003 to 2011. She had not become pregnant again despite having regular relations without contraception. Although her serum free and total testosterone, androstenedione, DHEA, and DHEA-S levels were normal, a diagnosis of PCOS was made by the Rotterdam criteria-the combination of oligomenorrhea plus clinical features of hyperandrogenism and the exclusion of CAH. The diagnosis was further supported by the findings of an elevated LH/FSH ratio and a low concentration of SHBG, which is evidence for both hyperandrogenism and insulin resistance. Although her baseline serum 25-OH-vitamin D3 level was normal at 34 ng/dl, her serum 1,25-(OH)2-vitamin D3 level was elevated at 81 pg/ml. The patient refused standard treatment for cysticercosis with albendazole and dexamethasone because several of her friends had experienced adverse drug reactions with this therapy.

We initiated treatment of her PCOS with a 1200 kcal reducing diet, daily 30 minute walks, and metformin 500 mg twice daily after breakfast and supper. On this treatment monthly menses resumed, but periods lasted for only 2 days each cycle. After the metformin dosage was increased to 850 mg twice daily monthly menses continued and periods now lasted for 4 days. Hirsutism and acne noticeably diminished, however, she still did not conceive despite continuing regular relations without contraception (Table 1).


**Table 1.** Parameters related to polycystic ovarian syndrome

**•** The amelioration of CAH by insulin-sensitizing approaches suggests that, as in PCOS,

**3. Parasitic endocrine disruption; polycystic ovarian syndrome induced by**

There is growing awareness of the role of environmental endocrine disrupters in human health and reproduction as well as in the health and reproduction of other species. Most of the research in this area has dealt with the menace of manmade endocrine disrupting chemicals (EDC's), such as phthalates and hydraulic fracking chemicals. We are also rediscovering the endocrine disrupting role of parasites, which have preyed upon our species since prehistoric times. An example of this appears in statues of the pharaoh, Akhnaton which have often portrayed him as a young man with rounded hips and gynecomastia. Some historical epi‐ demiologists have suggested that this feminized appearance might be the result of hepatic

The patient we reported was a 33 year old (at that time) Mexican woman G3P2012 with extensive neurocysticercosis, who was referred to our clinic for secondary oligomenorrhea, acne, and hirsutism [49]. She had no localizing neurologic signs and none of the cestodes directly involved the hypothalamus or the pituitary gland. There was no family history of PCOS. She had previously conceived three times without difficulty, followed by 2 normal

2003 to 2011. She had not become pregnant again despite having regular relations without contraception. Although her serum free and total testosterone, androstenedione, DHEA, and DHEA-S levels were normal, a diagnosis of PCOS was made by the Rotterdam criteria-the combination of oligomenorrhea plus clinical features of hyperandrogenism and the exclusion of CAH. The diagnosis was further supported by the findings of an elevated LH/FSH ratio and a low concentration of SHBG, which is evidence for both hyperandrogenism and insulin resistance. Although her baseline serum 25-OH-vitamin D3 level was normal at 34 ng/dl, her serum 1,25-(OH)2-vitamin D3 level was elevated at 81 pg/ml. The patient refused standard treatment for cysticercosis with albendazole and dexamethasone because several of her friends

We initiated treatment of her PCOS with a 1200 kcal reducing diet, daily 30 minute walks, and metformin 500 mg twice daily after breakfast and supper. On this treatment monthly menses resumed, but periods lasted for only 2 days each cycle. After the metformin dosage was increased to 850 mg twice daily monthly menses continued and periods now lasted for 4 days. Hirsutism and acne noticeably diminished, however, she still did not conceive despite

and was almost unchanged from

involvement by schistosomiasis, which has long been endemic in the Nile Valley.

insulin resistance is an integral part of the pathogenesis of the CAH's.

**neurocysticercosis**

114 Contemporary Gynecologic Practice

**3.2. PCOS induced by neurocysticercosis**

pregnancies and 1 elective abortion. Her BMI was 28.34 kg/m2

had experienced adverse drug reactions with this therapy.

continuing regular relations without contraception (Table 1).

**3.1. Background**

Units and reference ranges for the parameters given in the table: BMI, body mass index kg/m2 [20–25]; FSH, follicle stimulating hormone mIU/l (1.37–17.20); Insulin mIU/l (<17.0); LH, luteinising hormone IU/l (1.9–76.3); LH/FSH (≤1.0); SHBG, sex hormone binding globulin nmol/l (17–120).

In performing a literature review to ascertain if there could be an association between PCOS and cysticercosis, we learned from publications that the encysted forms of Taenia sp. are virtual steroid factories, producing such metabolites as androstenedione, testosterone, estradiol, and 17-OH-progesterone [50-56].

Morales-Montor et al., in discussing host gender preference in mammalian parasitoses, reporting that Taenia sp. exhibit a marked female host preference, and even more readily infect and reproduce in pregnant hosts. When they do infect a male host, they will feminize the host via estradiol production [55].

Given the host preference of this parasite, it would seem counterintuitive that the Taenia cestodes would produce the hyperandrogenic state of PCOS, until one remembers that PCOS is also a state of unopposed estrogen, characterized by such features as superficial cell predominance on vaginal cytology, cervical mucus ferning on low power microscopy, spinnbarkeit, and withdrawal bleeding after progesterone challenge.

#### **3.3. Treatment of cysticercosis with selective estrogen receptor modulators (SERMs)**

Vargas-Villavicencio et al. reported that treatment of mice infected with Taenia crassiceps with the SERM, tamoxifen, resulted in a rapid, dramatic 80% reduction in parasite burden in infected females and a 50% reduction in males [57]. Tamoxifen increased the Th1/Th2 ratio favoring increased expression of cellular immunity as well as being associated with a change in the cytokine pattern consistent with greater Th1 expression. They also reported that cultured Taenia crassiceps cestodes that were exposed in vitro to tamoxifen concentrations comparable with those achieved in human treatment died rapidly.

After again declining standard treatment of her neurocysticercosis with albendazole and dexamethasone, we discussed with our patient the work reported by Vargas-Villavicencio et al. and obtained her fully informed consent to initiate a course of treatment with another SERM, raloxifene 60 mg orally daily. Pregnancy and disorders predisposing to a hypercoagulable state were excluded before commencing treatment. Raloxifene, rather than tamoxifen, was chosen so as not to increase the patient's risk for endometrial cancer and because the former is known to exacerbate post-menopausal vasomotor symptoms in early post-menopausal women, suggesting that it readily crosses the blood/brain barrier, acting as an estrogen receptor antagonist within the central nervous system. Raloxifene was added to metformin 850 mg twice daily beginning on January 21, 2010. The patient was reminded of the need for reliable contraception since raloxifene is contraindicated during pregnancy.

When the patient returned to clinic on March 17, 2010 she reported apologetically that she had a positive home pregnancy test. Pregnancy was confirmed in our laboratory. She was referred to Family Planning Clinic for termination of pregnancy, because, as we re-explained to our patient, raloxifene is FDA Pregnancy Class X (should not be used in pregnancy) and therefore we could not assure her of the likelihood of a healthy baby. Raloxifene was discontinued in the event that she chose to continue the pregnancy.

A repeat brain MRI, performed on April 26, 2010 showed a diminution in the number, size, and viability of the cestodes (Figure 13).

**Figure 13.** MRI's showing effect of raloxifene treatment 60 mg/day on a patient with extensive neurocysticercosis

The total number of lesions fell from 37 to 33. Ten lesions shrank, 5 lesions resolved, 18 lesions appeared unchanged, 4 lesions enlarged, and only 1 new lesion appeared. Concomitantly, her serum 1,25-(OH)2-vitamin D3 fell from 81 pg/ml to 41 pg/ml (Figure 14), while her serum 25- OH-vitamin D3 only fell from 34 ng/ml to 30 ng/ml with raloxifene treatment.

erum calcitriol le

Ten lesions shran

from 37 to 33. T

60 mg/day on se

**Figure 14.** Effect of raloxifene 60 mg/day on serum calcitriol level in a patient with neurocysticercosis

On May 5, 2010 causes of calcit develop hyperca either the cestod 0 she agreed to tr triol mediated h alcemia, her app des themselves o reatment with a hypercalcemia ha parently increas or the surroundin 2 week standard ave been report ed 1-α-hydroxy ng host macropha d course of alben ed and reviewe ylation of 25-OH ages carrying ou ndazole and dexa d by Kallas et H-vitamin D3 ma ut 1-α-hydroxyla On May 5, 2010 she agreed to treatment with a 2 week standard course of albendazole and dexamethasone, which she tolerated well. Rare causes of calcitriol mediated hypercalcemia have been reported and reviewed by Kallas et al. [58] and, although our patient did not develop hypercalcemia, her apparently increased 1-α-hydroxylation of 25-OH-vitamin D3 may be explained by the same mechanism-either the cestodes themselves or the surrounding host macrophages carrying out 1-α-hydroxylation.

Our patient thus Neuro s illustrates sever ocysticercosis ce ral previously un estodes can have nknown features e several endocr Our patient thus illustrates several previously unknown features:

A t

greater Th1 ex concentrations c After again decl the work reporte SERM, raloxife commencing tre because the form readily crosses t to metformin 85 raloxifene is con When the patien was confirmed i our patient, ralo likelihood of a h A repeat brain M

xpression. They comparable with lining standard ed by Vargas-V ene 60 mg ora eatment. Raloxif mer is known to the blood/brain b 50 mg twice dai ntraindicated dur nt returned to clin in our laboratory oxifene is FDA healthy baby. Ra MRI, performed

y also reported h those achieved treatment of her Villavicencio et a ally daily. Preg fene, rather than o exacerbate pos barrier, acting as ly beginning on ring pregnancy. nic on March 17 y. She was referr Pregnancy Cla aloxifene was dis on April 26, 201

that cultured in human treatm r neurocysticerc al. and obtained gnancy and diso tamoxifen, was st-menopausal v s an estrogen rec n January 21, 20

Taenia crassice ment died rapidly cosis with albend her fully inform orders predispo s chosen so as no vasomotor symp ceptor antagonis 10. The patient

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discussed with e of treatment w ate were exclud for endometrial women, sugges tem. Raloxifene reliable contrace

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a positive home f pregnancy, bec therefore we co ue the pregnancy d viability of the

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s appeared unch pg/ml to 41 pg/m

amethasone, whi al. (58) and, alt ay be explained

human hosts inc f 25-OH-vitamin onary sarcoidosi induced PCOS i

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dazole and dexa med consent to i osing to a hype ot to increase th ptoms in early p st within the cent was reminded o

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**Figure 13**. MR

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The total numbe and only 1 new serum 25-OH-vi

**Figure 14.** Effec

is known to exacerbate post-menopausal vasomotor symptoms in early post-menopausal women, suggesting that it readily crosses the blood/brain barrier, acting as an estrogen receptor antagonist within the central nervous system. Raloxifene was added to metformin 850 mg twice daily beginning on January 21, 2010. The patient was reminded of the need for reliable

When the patient returned to clinic on March 17, 2010 she reported apologetically that she had a positive home pregnancy test. Pregnancy was confirmed in our laboratory. She was referred to Family Planning Clinic for termination of pregnancy, because, as we re-explained to our patient, raloxifene is FDA Pregnancy Class X (should not be used in pregnancy) and therefore we could not assure her of the likelihood of a healthy baby. Raloxifene was discontinued in

A repeat brain MRI, performed on April 26, 2010 showed a diminution in the number, size,

**Figure 13.** MRI's showing effect of raloxifene treatment 60 mg/day on a patient with extensive neurocysticercosis

OH-vitamin D3 only fell from 34 ng/ml to 30 ng/ml with raloxifene treatment.

The total number of lesions fell from 37 to 33. Ten lesions shrank, 5 lesions resolved, 18 lesions appeared unchanged, 4 lesions enlarged, and only 1 new lesion appeared. Concomitantly, her serum 1,25-(OH)2-vitamin D3 fell from 81 pg/ml to 41 pg/ml (Figure 14), while her serum 25-

contraception since raloxifene is contraindicated during pregnancy.

the event that she chose to continue the pregnancy.

and viability of the cestodes (Figure 13).

116 Contemporary Gynecologic Practice

	- **1.** the use of metformin reduced the insulin resistance/hyperinsulinemia, which in turn reduced the hyperandrogenism and resulted in restoration of normal menses and resolution of acne and hirsutism, concurrently with an increase in serum SHBG and a normalization of the LH/FSH ratio, but did not, by itself result in restoration of fertility.
	- **2.** addition of the SERM, raloxifene, by causing a less estrogenic milieu restored fertility (although this was an unintended consequence).
