Strategies For Preservation of Ovarian and Testicular Function After Immunosuppression

3/10/2014
Strategies for preservation of ovarian and testicular function after immunosuppression

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Abstract
Keywords
Biological characteristics of gonadal
Risk factors for gonadal toxicity from
Cyclophosphamide pharmacokinetic
Fertility preservation strategies in wo
Fertility preservation strategies in men
Conclusion
References
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Family Medicine: Dermatology Review
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American Journal of Kidney Diseases

Volume 43, Issue 5, May 2004, Pages 772781
Review
Strategies for preservation of ovarian and testicular function after

immunosuppression
Shona Pendse, MDa, Elizabeth Ginsburg, MDa, Ajay K Singh, MDa,
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DOI: 10.1053/j.ajkd.2004.01.008
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Abstract
Seattle, United States

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Conference
34 Dec 2014
Gonadal toxicity as a side effect of cyclophosphamide therapy is a common long-term problem in the
treatment of a variety of glomerular diseases. In both men and women treated with cyclophosphamide, the
consequences of infertility can have great physical and emotional consequences; thus, this issue often has
a critical role in the decision to decline treatment with cyclophosphamide. There exists a critical need for
Sydney, Australia
strategies for preservation of fertility in both men and women who require treatment with
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Tool for Discovering the Underlying
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4 Oct 2014
cyclophosphamide. This review explores emerging therapeutic options in this arena, which include sperm
and oocyte cryopreservation, medical treatments such as testosterone therapy for men and gonadotropinreleasing hormone agonist therapy for both men and women, and, finally, the relatively new strategy of
germ-cell transplantation for both ovarian and testicular tissue, which still remains in the experimental
Seattle, United States
stages.
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Keywords
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Immunosuppression; cytotoxic agents; glomerulonephritis; infertility; ovarian function; testicular function

GONADAL TOXICITY as a side effect of cyclophosphamide therapy is a common long-term problem in the
treatment of a variety of glomerular diseases, including lupus nephritis, idiopathic membranous
glomerulopathy, and focal and segmental glomerulosclerosis. Therapy with cyclophosphamide often lasts
several months to years and may entail cumulative doses in excess of 20 g. In women, cyclophosphamideinduced ovarian toxicity is heralded by the onset of irregular or infrequent periods and may progress to
amenorrhea and ovarian failure.1 It is of greatest significance to premenopausal women because it results
in infertility and premature ovarian failure (POF), both of which have significant emotional and physical
consequences. Conversely, in men, cyclophosphamide-associated toxicity often goes unnoticed until the
problem presents as a markedly low sperm count detected in the workup of a couple's infertility.2 and 3 The
risk for infertility is a major factor in the decision to decline treatment with cyclophosphamide, yet it occurs
at a time when alternative therapies of the potency and potential effectiveness of cyclophosphamide are
either unavailable or inadequately tested for the treatment of glomerular disease. Hitherto, most of the
experience in understanding the biological characteristics of cyclophosphamide gonadotoxicity comes
from the oncology literature, and little information among patients with nephritis treated with
cyclophosphamide is available. In counseling patients about the risk for infertility from cyclophosphamide,
it is important to understand the underlying biological characteristics of gonadal toxicity of
cyclophosphamide and risk factors that predicate the development of gonadal toxicity, as well as strategies
that might mitigate this risk.
Biological characteristics of gonadal toxicity of cyclophosphamide

Women
Oligomenorrhea often is observed after treatment with cyclophosphamide, although precise
epidemiological data are unavailable in the literature. Oligomenorrhea may be transient, with eventual
return to a normal menstrual cycle, or may progress to POF. Other markers, either transient or permanent,
include increased levels of gonadotropins and decreased estradiol levels. Both animal and human studies
have found reduced numbers of ovarian follicles after chemotherapy.4 Cyclophosphamide toxicity in
women may be caused by a direct effect on the oocyte or may indirectly affect the oocyte through an effect
on the supporting granulosa cells of the follicle, through gap junctions connecting these nursing cells to
the oocyte.1, 5, 6, 7, 8 and 9 Cross-linking of DNA occurs in granulosa cells of animals treated with
cyclophosphamide within 2 hours of administration, and increased nuclear size is observed, which is
thought to be a result of cell-cycle block in the G2 phase.1 Most data that are available relating to the effects
of cyclophosphamide on the human ovary come from the oncology literature. After exposure to these
agents, human ovaries have been found to be fibrosed, with destruction of follicles.1
http://www.sciencedirect.com/science/article/pii/S0272638604001295
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Men
Exposure to cyclophosphamide may result in severe gonadal damage in males. Spitz et al initially
described the entity of testicular damage from cytotoxic drugs in 1948 when they discovered azoospermia
at autopsy in 27 of 30 men treated with nitrogen mustard.2 Azoospermia is found in 50% to 90% of males
exposed to cyclophosphamide.6 Although the germinal epithelium is thought to be more sensitive to the
effects of cytotoxic agents than are Leydig's cells, many researchers have found evidence of Leydig's cell
dysfunction, with increased levels of luteinizing hormone (LH) and either reduced or normal levels of
testosterone.5, 8 and 9 In the male reproductive tract, cyclophosphamide has been shown to cause
changes in spermatogonia, Sertoli's cells, and inclusion bodies in spermatogonia. Kenney et al3 studied
the effects of high-dose cyclophosphamide in males treated for sarcoma in childhood. Of 17 patients in the
study, 10 patients had azoospermia and 5 patients had oligospermia, whereas only 2 patients, both
administered the lowest doses of cyclophosphamide (<7.5 g/m2), had normal sperm counts. Testosterone
levels were normal in 15 patients. However, baseline LH (in 6 patients) and gonadatropin-releasing
hormone (GnRH)stimulated LH levels were elevated (>3 times baseline values in 13 patients), consistent
with Leydig's cell involvement.
Risk factors for gonadal toxicity from cyclophosphamide

Advanced age
Advanced age has been shown to modulate the risk for cyclophosphamide-related gonadal dysfunction.
Older women are more likely to progress to POF after therapy because they have a smaller number of
oocytes at initiation of chemotherapy. Younger women, although frequently able to return to normal
ovarian function after a course of cyclophosphamide therapy, are likely to eventually undergo POF.10 In
patients with lupus nephritis, cyclophosphamide therapy resulted in ovarian failure in 100% of women older
than 30 years, approximately 50% of those aged 20 to 30 years, and 13% of patients younger than 20
years.11 In a study of female patients treated with cyclophosphamide for breast cancer, the average
cumulative dose needed to effect amenorrhea decreased with age, with doses of 20.4 g in women in their
20s, 9.3 g in women in their 30s, and as little as 5.2 g for women in their 40s.1 and 12
High cumulative cyclophosphamide dose

Higher cumulative doses of cyclophosphamide also have been associated with increased risk for the
development of gonadal toxicity. Boumpas et al13 evaluated 16 patients administered 7 monthly pulses of
cyclophosphamide and 23 patients administered 15 or more cyclophosphamide pulses. Two of the 16
patients in the lower-cumulative-dose arm developed sustained amenorrhea in contrast to 9 of 23 patients
in the higher-dose arm. Three patients had transient amenorrhea, and all these occurred in the lowercumulative-dose arm. Long-term follow-up showed 2 full-term pregnancies with delivery of healthy
newborns and 4 elective abortions in the short-cyclophosphamide arm, whereas the longcyclophosphamide arm had no pregnancies.
Cyclophosphamide pharmacokinetics and dosing in the setting of renal dysfunction

In patients with acute glomerulonephritis administered cyclophosphamide, dosing of cyclophosphamide is
challenging because of the need for dose adjustment in the setting of renal dysfunction.
Cyclophosphamide is a prodrug extensively metabolized to form both active (alkylating) and inactive
byproducts.14, 15, 16, 17, 18 and 19 Both byproducts and approximately 25% of the original parent
compound are eliminated from the body through the kidneys.15 and 18 However, although
cyclophosphamide often is used in the setting of renal dysfunction, data are minimal regarding the effects
of impaired renal clearance on cyclophosphamide levels and toxicity. In addition, data are conflicting.
Some investigators reported reduced cyclophosphamide clearance in the setting of impaired renal
function20, 21 and 22 in conjunction with increased toxicity,20 whereas others suggested there are no
changes in drug levels with renal dysfunction.18, 19 and 23
A recent investigation by Haubitz et al16 in 2002 reported a significant difference in cyclophosphamide
clearance in the setting of both renal dysfunction and hemodialysis. They evaluated 15 patients with
autoimmune diseases and a creatinine clearance (Ccr) less than 50 mL/min (<0.83 mL/s) who were
scheduled for pulse cyclophosphamide therapy, divided into subsets of patients with Ccr of 25 to 50
mL/min (0.42 to 0.83 mL/s) and 10 to 24 mL/min (0.17 to 0.40 mL/s), and a third group composed of
patients with a Ccr less than 10 mL/min (<0.17 mL/s) in the setting of hemodialysis treatment. Their results
suggest significant change in cyclophosphamide pharmacokinetics with both reduction in renal clearance
and hemodialysis. A 42% increase in systemic drug exposure in patients with a Ccr of 25 to 50 mL/min
(0.42 to 0.83 mL/s) was observed compared with controls versus a 77% increase in the group with a Ccr of
10 to 24 mL/min (0.17 to 0.40 mL/s). Systemic clearance of cyclophosphamide was reduced by 28% (P <
0.01) and 41% (P < 0.001) compared with controls, respectively. Furthermore, a rapid decrease in serum
concentrations of drug with dialysis was observed, suggesting effective clearance with hemodialysis. In
addition, nearly 22% of the original administered dose of the drug was excreted into the dialysate after a 3hour dialysis run, further confirming effective clearance. These investigators recommended a 20% to 30%
reduction in drug dosage, depending on degree of renal impairment.
These data confirm earlier findings by Juma et al,21 who observed a 17% decrease in clearance and 24%
increase in half-life of cyclophosphamide in 6 patients with a Ccr of 18 to 51 mL/min (0.30 to 0.85 mL/s)
compared with 8 matched control subjects.
An earlier investigation by Wang et al24 evaluated cyclophosphamide pharmacokinetics in the setting of
dialysis, and these investigators reported a 37% clearance rate during the course of a 4-hour hemodialysis
2/26
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run. That cyclophosphamide is a small nonionized molecule with low protein binding supports this
characteristic of efficient dialyzability.16
The issue of when to dialyze after drug administration remains controversial. Wagner et al25
recommended dialysis as soon as 2 hours after cyclophosphamide administration, whereas Haubitz et
al16 recommended that dialysis not be performed for a minimum of 12 hours after administration to allow
for adequate immunosuppression.
Fertility preservation strategies in women

The risk for POF represents one of the major long-term sequelae of gonadotoxic chemotherapeutic agents.
Given the female predominance of such autoimmune disorders as systemic lupus erythematosus (SLE),
this issue is of particular importance in the care of female patients. Of these agents, cyclophosphamide has
been the most studied.26, 27, 28 and 29
The majority of follicles in the human ovary are in a quiescent state, known as primordial follicles, and
treatment with cytotoxic agents results in apoptosis of these follicles. Because these follicles cannot by
regenerated, this follicular destruction results in POF. Alkylating agents also have been shown to result in
ovarian fibrosis, increases in follicle-stimulating hormone (FSH) and LH levels, and decreases in estradiol
levels.30 and 31 These changes, in turn, result in hypergonadotropic hypogonadism and consequent
amenorrhea, with the possibility of eventual POF.1 Because older patients have fewer oocytes, even
before the initiation of cyclophosphamide therapy, they have a greater likelihood of eventual ovarian failure
then their younger counterparts.1 and 2 In a study of female patients with lupus nephritis, POF was
observed in half the patients treated with cyclophosphamide pulse therapy; 100% of women older than 30
years, 50% of women aged 20 to 30 years, and 13% of patients younger than 20 years developed POF.11,
26 and 32
Expansion of the indications for such chemotherapeutic agents to include autoimmune disorders, affecting
large numbers of young female patients, has dramatically increased the need for strategies for ovarian
function preservation.
Cryopreservation of embryos and oocytes

Cryopreservation of embryos and, less commonly, oocytes has been the mainstay of ovarian preservation
until recent trials with GnRH agonist (GnRHa). Oocyte cryopreservation can be divided further into banking
of mature (metaphase II) oocytes, germinal vesicle oocytes, and isolated primordial follicles.33 Of these,
cryopreservation of embryos has been more successful than that of oocytes.2 and 29 Newer techniques of
egg retrieval after controlled ovarian hyperstimulation and in vitro fertilization (IVF) continue to increase the
likelihood of success with these endeavors.34 and 35 However, this strategy usually is possible only with
female patients who have already selected a partner or those willing to use donor sperm.
However, in contrast to embryo cryopreservation, oocyte cryopreservation remains difficult because the
freeze-thaw techniques used at present appear to greatly inhibit survival and fertilizability of the frozenthawed eggs. Survival rates of oocytes after the freeze-thaw process have been between 18% and
50%,36 and 37 with fertilization rates less than 50%.38 Possible theories for the poor outcome of
cryopreserved oocytes include hardening of the zona pellucida during the course of cryopreservation,
resulting in inhibition of sperm penetration,39 and 40 and depolymerization of the spindle apparatus with
cooling, resulting in chromosomal loss and consequently aneuploidy after the first maturation division.33,
37, 41 and 42
The technique of preimplantation genetic diagnosis recently was suggested as a mechanism to circumvent
the potential outcomes of such genetic instability by allowing for the early detection of genetic disorders in
the setting of cryopreservation and IVF. However, the process of such genetic diagnosis necessitates
opening the zona pellucida and removing 1 or more blastomeres (embryo biopsy), which in itself is thought
to be detrimental to survival of the embryo because of a decrease in implantation ability.43, 44, 45 and 46
Preimplantation genetic diagnosis does not increase survival of oocytes in the freeze-thaw process, but
rather is intended to decrease the transfer of abnormal embryos. Maximization of survival after
cryopreservation is an area under intense investigation by many groups, which includes variation in both
type of cryoprotectant and rate of cooling. Types of cryoprotectants include dimethyl sulfoxide (DMSO),
glycerol, and propanediol.33, 43, 47 and 48 Recent work suggests that exposure to high sucrose
concentrations improves survival.43, 47 and 48 There also is evidence that suggests lower sodium content
in the medium decreases the degree of osmotic shifts, thereby improving survival.49 With regard to cooling
time, slower rates of cooling and rapid thawing have been associated with improvement in survival by
minimizing ice formation within the cells.33, 47 and 48
An alternative to storing mature oocytes in metaphase II is to do so when they have reached full size and
are able to undergo meiosis, but before they reach metaphase II. At this stage, these germinal vesicle
oocytes, because of the absence of a spindle apparatus, carry a decreased risk for chromosomal
alterations.33 However, the risk for zona pellucida hardening as a result of the freeze-thaw process is still
present.33 These germinal vesicle oocytes must then be matured in vitro. Although this has been done in
mice,50 optimal conditions for this maturation process after cryopreservation in human oocytes still need to
be found, thus leaving this option in experimental stages.33
Banking of isolated primordial follicles is another alternative in this process. Primordial follicles are smaller
than more mature oocytes, are less differentiated, have fewer organelles, and do not have a zona
pellucida, all beneficial in surviving the freeze-thaw process.33 Oktay et al51 assessed the viability of these
primordial follicles after a freeze-thaw process. They cryopreserved 2- 2-cm ovarian cortical pieces by
using a slow freeze process, after which they thawed the tissue, digested them with collagenase, and
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subsequently dissected the follicles. Viability studies showed 70% of follicles to be viable. On electron
microscopy, the basement membrane of the follicle was damaged secondary to the digestion process, but
the oocytes were preserved. These follicles can be stored after digestion into individual follicular units or as
thin slices of ovarian tissue, as in this case.33 Although this has resulted in fertility in animals,52, 53 and 54
it also is in experimental stages in humans.33
Medical techniques for fertility preservation

The observation that prepubertal patients undergoing chemotherapy have a lower rate of permanent
gonadal dysfunction has led to many trials of suppression of ovarian cycling, with the aim toward inducing a
prepubertal state that is less sensitive to the effects of these agents.4, 10, 55 and 56 This is based on
evidence from long-term cancer survivors suggesting that women treated with chemotherapy in their
prepubertal years had greater preservation of ovarian function after treatment57, 58 and 59 than adult
women treated with similar therapy.60 and 61 Toward this end, GnRHas have been used to induce ovarian
suppression in both animal and human trials.
In rat models of cyclophosphamide-induced ovarian dysfunction, GnRHas administered several weeks
before the initiation of cyclophosphamide therapy resulted in decreased recruitment of follicles into a
growth phase.62, 63 and 64 Decreased tritiated thymidine uptake consequent to GnRHa administration
also was observed, indicating decreased proliferation.27, 65 and 66 Furthermore, this GnRHa-induced
inhibition was greater in female than male rats.27 These investigators showed a similar protective effect of
GnRH in the primate model. They found that female Rhesus monkeys administered a GnRHa in
conjunction with cyclophosphamide had a significant decrease in daily follicular loss than their
counterparts who were administered cyclophosphamide alone.63 Current evidence has shown a similar
protective effect in humans.
Blumenfeld et al32 administered a monthly injection of depot-GnRHa in conjunction with chemotherapy to
8 women with autoimmune, severe, connective tissue disorders (7 patients, SLE; 1 patient, nephrotic
syndrome). Compared with a control group of 9 patients with similar autoimmune disorders treated with
chemotherapy alone, none of the GnRHa-treated patients had POF (defined by amenorrhea, estradiol
level < 100 pmol/L, and FSH level > 25 IU/L), whereas 5 of 9 patients treated with chemotherapy alone had
POF. They did this as a follow-up to their earlier trial using the same monthly depot-GnRHa in conjunction
with chemotherapy in 18 women with Hodgkin's or non-Hodgkin's lymphoma and 18 historic matched
control patients with lymphoma treated with chemotherapy alone.67 Of 16 patients in the GnRHa group
who completed the study (2 patients failed to enter remission and died of the disease), 15 patients resumed
ovarian cycling, with menses and ovulation 3 to 8 months after conclusion of the combination treatment.
However, in the control group, only 7 of 18 patients who completed the protocol using chemotherapy alone
had return of menses and ovulation. The remaining 11 patients had ensuing ovarian failure and POF. Mean
FSH levels were 12.5 16.4 IU/L in the GnRHa group and 36 25.2 IU/L in the control group. Mean age
was 23.1 6.7 years in the GnRHa group and 25.8 7.8 years in the control group.
One risk that must be mentioned in the treatment of patients with SLE is that of precipitating a disease flare
with hormonal stimulation. This has been described by several investigators, including Metcalfe and
Boulton-Jones,68 who published a case report of a 37-year-old woman with class IV lupus nephritis who, 3
weeks after her first dosage of leuprorelin for uterine leiomyoma, had flares of both her systemic and renal
lupus disease activity. Other investigators also described serious flares in patients with SLE,69 including
an investigator who described a flare of SLE-associated thrombocytopenia.70 This has been suggested to
result from GnRH receptor expression on immune cells.71 and 72 Furthermore, they found differential
expression with regard to sex: GnRH exacerbated lupus in vivo in female mice alone,73 and GnRH
resulted in T-cell proliferation in vitro in females alone, as well.71, 72 and 74 Because GnRH acts through
signal-transducing G proteins, they then looked for differential expression in these and found that immune
effector cells from female rats expressed greater amounts of G proteins than cells from males.72
Germ cell transplantation for fertility preservation

One final strategy that remains in experimental stages is cryopreservation of ovarian cortical strips with
subsequent reimplantation after chemotherapy to either the pelvic cavity or a heterotopic site (for egg
retrieval and in vitro techniques).75 Gosden et al76 showed that ovarian grafting in castrated sheep
resulted in a return of cyclic ovarian activity and fertility for up to 22 months after implantation. Harp et al77
found that autologous implantation of cryopreserved ovarian tissue with DMSO at 196C successfully
restored cyclic ovarian activity in 75% of ovariectomized mice, similar to control recipients into which fresh
ovarian grafts were implanted.
Liu et al78 transplanted frozen-thawed newborn murine ovaries into 10- to 12-week-old female mice and
subsequently removed the grafts 14 days posttransplantation, after which they isolated individual follicles
and cultured them in vitro for 12 days. After induction of final maturation with human chorionic
gonadotropin, the oocytes were fertilized in vitro and the 3-day-old embryos were implanted into
pseudopregnant females, resulting in the birth of healthy newborns.42 and 78
Such therapies are now being extended to human trials. However, one of the difficulties in making the
transition from animal trials to humans is that in vitro growth of follicles is slower in humans. In contrast to
murine primordial follicles, which can take 20 to 30 days to attain maturity, similar maturation of human
follicles often requires in excess of 90 days.41 Radford et al75 performed this surgical grafting in a 36-yearold woman undergoing chemotherapy for Hodgkin's disease, as the first patient in a 20-patient phase I/II
trial currently underway. The investigators published a case report of the first patient enrolled in their study
who, after reimplantation of the cortical strips, had decreases in FSH and LH levels and an increase in
estradiol level, along with resolution of hot flashes and return of menses up to 9 months after implantation.
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However, after this time, she progressed to ovarian failure. Oktay et al51 also initiated the first phase of a
trial in ovarian transplantation. Their first patient, 32 years of age, had ovarian tissue grafted into the
forearm. Four months after the procedure, she was noted by means of ultrasound to have development of
antral follicles in the forearm, and estradiol production by the graft was detected.51 In the second patient of
this study, frozen tissue that was thawed after 8 months of storage was transplanted. Four months after
transplantation, the patient experienced ovulation in response to induction by exogenous
gonadatropins.51
However, one risk with such transplantation in patients with malignancies is the risk for reseeding of cancer
cells along with the tissue; thus, this may serve as a better option for those with autoimmune disorders
treated with cyclophosphamide.79 and 80 In patients with cancer wishing to undergo such transplantation,
histological evaluation using multiple samples must be performed, along with immunohistochemical,
genetic, or molecular techniques to look for evidence of cancer cells within the ovaries before
transplantation.49
Initially, it was thought that cryopreservation resulted in destruction of follicles. However, recent work
suggests it is not the initial cryopreservation, but rather the ischemia that occurs with transplantation, that
results in this follicular loss.75, 81 and 82 Thus, investigations directed toward finding avenues for
hastening revascularization have been undertaken by many, including such substances as vitamin E and
exogenous gonadotropins.83
Fertility preservation strategies in men

Several glomerular diseases have an equal or greater propensity to affect males than females. These
diseases include focal segmental glomerulosclerosis, membranous glomerulopathy, and immunoglobulin
A nephropathy. Other diseases, such as lupus nephritis, occur in males, but rarely. In addition, infertility
from such gonadotoxic agents as cyclophosphamide has been found to be more frequent in men than
women because of increased susceptibility of the testis to the effects of chemotherapy.2 and 29 Therefore,
numerous investigations have been aimed at identifying strategies for preservation of fertility. Preventing
testicular dysfunction therefore is very important. The most common strategies include sperm
cryopreservation and use of testosterone to shut down testicular function.
Sperm cryopreservation
Cryostorage of semen has become a standard of practice and is offered routinely to men undergoing
gonadotoxic chemotherapy.84, 85 and 86 However, this is not a viable option for prepubertal patients.
Another point of difficulty with this mode of treatment is that testicular function can be impaired even before
chemotherapy in patients with systemic disease, leading to poor sperm quality and sperm
counts.84 and 86 Although this has been shown in patients with malignant disease by numerous
investigators, a recent study by Ranganathan et al84 assessed this in 23 men with nonmalignant
nontesticular disorders. They found that precryopreservation semen samples were of poorer quality that
those of healthy donors, but were within normal World Health Organization (WHO) reference values.
Comparison of semen quality between patients with different disorders showed no statistically different
differences. Serum characteristics after cryopreservation also were within the WHO reference range.
Seven patients had adequate numbers of motile sperm for multiple intrauterine insemination procedures,
and the remaining patients had adequate semen for other reproductive techniques, such as IVF and
intracytoplasmic sperm injection. Given these newer techniques, successful fertilization may be achieved
with only minimal numbers of viable sperm.2 and 87
Medical techniques for fertility preservation

Similar to attempts for preservation of fertility in females,4, 10, 55 and 56 a prevailing thought has been of
creating a prepubertal state that, given its quiescence, remains relatively resistant to destruction by
gonadotoxic agents.3, 6, 7, 37, 55, 56 and 88 Although this has been shown by several investigators using
animal models, data for humans are limited. Ward et al89 found nearly normal sperm counts at 90 days in
procarbazine-treated rats administered the GnRHa goserelin (Zoladex; AstraZeneca Pharmaceuticals,
Wilmington, DE) beginning 2 weeks before chemotherapy and continued throughout the duration of
chemotherapy. Compared with rats treated with procarbazine alone, rats treated with the GnRHa had
significantly greater sperm counts. Similar effects have been found using testosterone, alone90 or in
conjunction with either a GnRHa91 or estradiol,92 and GnRHa in conjunction with the antiandrogen
flutamide.93
One recent human trial showing a protective effect of testosterone was performed by Masala et al.6 They
randomly divided 15 men with glomerulonephritis into 3 groups: the first group was administered daily oral
cyclophosphamide; the second group, monthly intravenous (IV) cyclophosphamide; and the third group,
testosterone, 100 mg intramuscularly every 15 days, beginning 30 days before initiation of IV
cyclophosphamide. All patients administered daily oral cyclophosphamide and 4 of 5 patients administered
IV cyclophosphamide had azoospermia at 6 months after discontinuation of therapy, whereas only 1 of 10
patients had normalization of the sperm count at this time. FSH levels were elevated, with mean levels of
19.20 1.28 IU/L in the oral-cyclophosphamide group and 16.04 2.22 IU/L in the IV-cyclophosphamide
group, suggesting significant effect on testicular function. Conversely, sperm counts and motility returned
to normal by 6 months after therapy in the 5 patients administered testosterone before and during
chemotherapy. In addition, FSH levels remained within the normal range in these patients, with a mean
FSH level of 5.08 0.56 IU/L. The difference in FSH levels between the patients in the testosterone group
versus the other 2 groups was statistically significant. LH levels were normal in patients in all 3 groups,
suggesting that Leydig's cell function was not affected.
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Germ-cell transplantation for fertility preservation
A third method for preserving testicular function remains in the experimental stage. In 1994, Brinster and
Zimmermann94 found that germ cells isolated from a donor mouse could be injected into the seminiferous
tubules of a sterile recipient mouse, resulting in successful spermatogenesis. These investigators more
recently showed that injection of cryopreserved donor germ cells into a sterile recipient mouse also
resulted in successful spermatogenesis. As in females, one risk with very serious consequences for
patients with cancer is that of reseeding cancer cells with the transfer of germ-cell tissue, thus
necessitating thorough screening before embarking on this course of therapy.49
Conclusion
Cyclophosphamide treatment is associated with infertility in both males and females administered large
cumulative doses. More research is needed concerning techniques to maintain ovarian and testicular
function after cyclophosphamide treatment. Currently, the limited data available indicate that use of a
GnRHa during treatment may partially protect ovarian function. Pretreatment cryopreservation of sperm
should be considered the standard of care in men. For selected women, a cycle of IVF with embryo
cryopreservation, which is proven therapy, may be appropriate, followed by treatment with GnRHa
therapy. It also is important to note that treatment with a GnRHa should be initiated 1 to 2 weeks before the
initiation of chemotherapy because, during this period, the stimulated gonadal tissue may be rendered
more susceptible to the toxic effects of chemotherapy.29 Oocyte or ovarian tissue cryopreservation is still
not well established and should be undertaken only in well-run research protocols, with patients clearly
informed about the minimal prospective and outcomes data available. Thus, early referral of patients to a
reproductive endocrinologist is critical to the timely initiation of such interventions should they be desired.
Early discussion by the treating nephrologist about the possible effects of chemotherapy on fertility,
followed by referral as early as possible in the course of therapy, is at the core of management of these
issues.
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Strategies For Preservation of Ovarian and Testicular Function After Immunosuppression

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Strategies for preservation of ovarian and testicular function after immunosuppression

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American Journal of Kidney Diseases

Strategies for preservation of ovarian and testicular function after

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Seattle, United States

Organic Acids Testing: An Invaluable

Seattle, United States

Immunosuppression; cytotoxic agents; glomerulonephritis; infertility; ovarian function; testicular function

Biological characteristics of gonadal toxicity of cyclophosphamide

Strategies for preservation of ovarian and testicular function after immunosuppression

Risk factors for gonadal toxicity from cyclophosphamide

High cumulative cyclophosphamide dose

Cyclophosphamide pharmacokinetics and dosing in the setting of renal dysfunction

Strategies for preservation of ovarian and testicular function after immunosuppression

Fertility preservation strategies in women

Cryopreservation of embryos and oocytes

Strategies for preservation of ovarian and testicular function after immunosuppression

Medical techniques for fertility preservation

Germ cell transplantation for fertility preservation

Strategies for preservation of ovarian and testicular function after immunosuppression

Fertility preservation strategies in men

Medical techniques for fertility preservation

Strategies for preservation of ovarian and testicular function after immunosuppression

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Strategies for preservation of ovarian and testicular function after immunosuppression

J Byrne, T.R Fears, M.H Gail, et al.

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A.V Boddy, S.M Yule

D Busse, F.W Busch, F Bohnenstengel, et al.

M Haubitz, F Bohnenstengel, R Brunkhorst, M Schwab, U Hofmann, D Busse

M Haubitz, S Schellong, U Gobel, et al.

L.B Grochow, M Colvin

C.M Bagley Jr, F.W Bostick, V.T DeVita Jr

F.D Juma, H.J Rogers, J.R Trounce

H.T Mouridsen, E Jacobsen

Strategies for preservation of ovarian and testicular function after immunosuppression

V Bramwell, R.T Calvert, G Edwards, H Scarffe, D Crowther

L.H Wang, C.S Lee, B.L Majeske, T.C Marbury

T Wagner, D Heydrich, H Bartels, H.J Hohorst

P Langevitz, L Klein, M Pras, A Many

Z Blumenfeld, I Avivi, M Ritter, J.M Rowe

gonadotoxicity in young women

W.J Gradishar, R.L Schilsky

G.L Warne, K.F Fairley, J.B Hobbs, F.I Martin

Z Blumenfeld, D Shapiro, M Shteinberg, I Avivi, M Nahir

K Oktay, H Newton, Y Aubard, O Salha, R.G Gosden

Z Blumenfeld, T Amit, R.J Barkey, B Lunenfeld, J.M Brandes

Z Blumenfeld, R.J Barkey, M.B Youdim, J.M Brandes, T Amit

Strategies for preservation of ovarian and testicular function after immunosuppression

J Mandelbaum, A.M Junca, M Plachot, et al.

J.E Hunter, A Bernard, B Fuller, N Amso, R.W Shaw

C Vincent, S.J Pickering, M.H Johnson

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