Table V.

Summary of evidence on markers of reproductive ability in female and male childhood or adolescent Hodgkin lymphoma survivors.

Reported outcome	N studies	N HL survivors	Results
Females	41	5057
Serum anti-Müllerian hormone (AMH)	6	180	Pre-treatment 9% of newly diagnosed HL patients had low AMH levels (<p10); 1 study; 32 patients
			Post-treatment 55–59% of studied HL survivors had low AMH levels (<14 pM or <95% CI of healthy controls) after treatment, none of the studied patients had received pelvic radiotherapy; 2 studies; 46 patients A significant decrease in AMH before and after treatment was reported; 3 studies; 89 patients AMH serum levels were lower in patients treated with MOPP, when compared to patients that did not receive MOPP; 1 study; 17 patients
Antral follicle count (AFC)	1	44	Post-treatment A significant decrease in AFC before and after treatment was reported; 1 study; 13 patients
Premature ovarian insufficiency (POI)*	7	1516	Post-treatment Survivors with POI ranged from 6% to 34% (median 9%); 7 studies; 1516 patients POI was observed more often or sooner if HL treatment included (high) doses of ovarian radiotherapy; 2 studies; 912 patients
‘Ovarian failure’ (not defined)	3	154	Post-treatment Ovarian failure was reported in 13–31% (median 17%); 3 studies; 154 patients Ovarian failure was observed more frequently in patients who had received pelvic radiation; 1 study; 36 patients
Acute ovarian failure (AOF)	1	553	Post-treatment 12% of the included females reported never menstruating or ceased having spontaneous menses within 5 years after cancer diagnosis; 1 study; 553 patients
Cycle (ir)regularity or amenorrhea	18	387	Post-treatment Majority of HL survivors developed or maintained regular menstrual cycles (range 79–100%, median 100%); 9 studies; 168 patients Survivors experiencing amenorrhea post-treatment ranged from 0% to 71% (median 4%); 13 studies; 240 patients Cycle irregularity was observed more frequently in patients treated with MOPP, when compared to patients that had received other chemotherapy protocols; 1 study; 16 patients 3 patients developed amenorrhea during therapy, but resumed spontaneous menses 2–4 years post-treatment; 1 study; 36 patients
Serum follicle stimulating hormone (FSH)	8	155	Post-treatment 17–100% (median 53%) of HL survivors had elevated FSH (above cutoff value 8–30 IU/l, or high in comparison to healthy controls or survivors of other types of childhood cancer); 7 studies; 132 patients A significant increase in serum FSH levels before and after treatment was reported; 1 study; 13 patients FSH serum levels were higher in patients who received pelvic radiotherapy; 4 studies; 55 patients FSH serum levels were higher in patients who received higher cumulative doses of procarbazine/MOPP; 2 studies; 44 patients In 4 patients, FSH values normalized over time, at 2–9 years post-treatment; 1 study; 14 patients
Pregnancy or live birth	20	2681	Post-treatment Pregnancy or live birth was reported in 1262 out of 2388 (53%) females; 19 studies; 2388 patients A significant lower ratio of observed to expected number of live born children was reported in 110 married/cohabitant HL-surviving women, in comparison to general population, ratio 0.53: 95% CI 0.42–0.64; 1 study; 110 patients The proportion of mothers in HL survivors was comparable to a general population group, except for the age group 40–44 years old (61% of 66 HL survivors versus 78% of 2.847.000 women, P = 0.001); 1 study; 467 patients A negative association was seen between parenthood and pelvic radiotherapy; 1 study; 467 patients Median time to pregnancy was 42 months (3–100 months); 1 study; 26 patients There were no statistically significant differences in pregnancy outcomes observed in patients with or without ovarian transposition; 1 study; 90 patients. The number of pregnancies achieved via IUI or IVF were n = 4/176, n = 2/17, and n = 1/10, respectively; 3 studies; 277 patients
Males	52	1903
Semen-analysis	39	1118	Pre-treatment Incidence of azoospermia in newly diagnosed HL patients ranged from 0% to 50% (median 10%); 6 studies; 109 patients Incidence of oligospermia in newly diagnosed HL patients ranged from 39% to 68% (median 55%); 3 studies; 43 patients
			Post-treatment Incidence azoospermia in HL survivors ranged from 33% to 100% (median 75%); 29 studies; 332 patients Incidence oligospermia in HL survivors ranged from 0% to 33% (median 17.5%); 14 studies; 223 patients Higher incidences of abnormal sperm counts were observed in patients who had received MOPP when compared to patients receiving other chemotherapy treatments; 2 studies; 34 patients No recovery of sperm was seen in 19 HL survivors, up to 20 years post-treatment; 1 study; 19 patients 3 azoospermic and 2 oligospermic patients had late recovery (at 30, 57, 108, 18, and 19 months post-treatment, respectively); 1 study; 20 patients Semen analysis of 2 HL survivors showed late recovery (at 12 years post-treatment), the remaining 10 azoospermic boys had no recovery up to 14 years post-treatment; 1 study; 19 patients 2 azoospermic and 2 oligospermic patients had late recovery (at 14, 127, 41, and 103 months post-treatment, respectively); 1 study; 12 patients
Serum follicle stimulating hormone (FSH)	28	738	Pre-treatment Mean serum FSH values were significantly higher in HL patients, when compared to healthy controls; 1 study; 10 patients
			Post-treatment Percentage of HL survivors with elevated FSH ranged from 0% to 100% (median 51.5%) (applied cutoff values ranged from >5 to >18 IU/l or >2 SD of controls); 26 studies; 672 patients Median serum FSH values were significantly higher and more often above cutoff in HL patients treated with MOPP, when compared to patients that did not receive MOPP; 2 studies; 89 patients Elevated FSH levels were observed more frequently in (post)pubertal boys, when compared to pre-pubertal boys; 2 studies; 33 patients FSH levels remained elevated up to 17 years post-treatment; 1 study; 28 patients FSH levels remained unchanged up to 8 years post-treatment; 1 study; 36 patients 1 out of 4 patients had a normalizing FSH value over time; 1 study; 4 patients In 2 patients a significant decrease in FSH value was observed over time (9–10 years post-treatment); 1 study; 20 patients
Serum Inhibin B	5	182	Pre-treatment Mean serum Inhibin B values were significantly lower in HL patients, when compared to healthy controls; 1 study; 10 patients
			Post-treatment Percentage of HL survivors with both elevated FSH and low inhibin B was 45–50% (median 47,5%) (applied cutoff <100 pg/ml); 2 studies; 95 patients 4 out of 21 HL survivors (19%) had low inhibin B serum levels (applied cutoff <100 pg/ml); 1 study; 21 patients Median inhibin B levels were significantly lower in patients treated with MOPP, when compared to patients that did not receive MOPP; 1 study; 56 patients
Serum luteinizing hormone (LH)	24	604	Pre-treatment Mean serum LH values were significantly higher in HL patients, when compared to healthy controls; 1 study; 10 patients
			Post-treatment Percentage of HL survivors with elevated LH levels ranged from 0 to 57% (median 17%) (applied cutoff values ranged from >3 to >30 IU/l or >2 SD of controls); 21 studies; 528 patients Percentage of HL survivors with low LH levels ranged from 0 to 33% (median 0%) (applied cutoff values ranged from <0.9 up to <5 U/l); 6 studies; 75 patients Median serum LH values were significantly higher in HL patients treated with MOPP, when compared to patients that did not receive MOPP; 1 study; 56 patients Elevated LH levels were observed more frequently in late pubertal patients, when compared to pre-pubertal boys; 1 study; 15 patients Elevated LH levels were observed more frequently in patients received a more intensified chemotherapy regimen (i.e. more courses of COPP); 1 study; 65 patients. The proportion of patients who had received abdominal radiotherapy was higher among patients with elevated LH levels, when compared to patients with normal LH levels; 1 study; 49 patients. In 2 patients, LH levels were initially elevated, but returned to normal over time (6 and 11 years post-treatment). In 8 other patients, LH levels were initially within normal range, but subsequently became elevated over time (up to 12 years post-treatment); 1 study; 40 patients
Serum testosterone	21	498	Pre-treatment There were no statistically significant differences in mean serum testosterone levels of newly diagnosed HL patients and controls; 1 study; 10 patients.
			Post-treatment Serum testosterone levels were within normal range; 3 studies; 79 patients There were no statistically significant differences in mean serum testosterone levels of HL survivors and controls; 1 study; 25 patients Mean testosterone levels were higher in HL survivors when compared to controls; 1 study; 45 patients There were no statistically significant differences in median serum testosterone levels of patients treated with MOPP and patients that did not receive MOPP; 1 study; 56 patients 0–43% (median 6%) of HL survivors had low testosterone serum levels (applied cutoff values ranged from <0.1 to <14 IU/l, or <2 SD of controls); 15 studies; 339 patients 0–33% (median 16,5%) of HL survivors had high testosterone serum levels (>35 nmol/l); 2 studies; 22 patients
Pregnancy or live birth	13	755	Post-treatment Pregnancy or live birth was reported in 374 out of 656 (57%) males; 13 studies; 656 patients 5 out of 24 (21%) patients with signs of germinal epithelium damage (e.g. elevated FSH levels) have children; 1 study; 24 patients None of 11 male HL survivors used their stored sperm; 1 study; 11 patients

AFC, antral follicle count; AOF, acute ovarian failure; AMH, anti-Müllerian hormone; HL, Hodgkin lymphoma; MOPP, Mechlorethamine, Vincristine (Oncovin), Procarbazine, Prednisone; N, number; POI, premature ovarian insufficiency.

^*All reports on (premature) ovarian failure before the age of 40 years, sometimes within papers referred to as non-surgical premature menopause (NSPM), were defined as POI in this review.